Circular RNAs (circRNAs) perform critical functions in cancer biology, commonly serving as microRNA (miRNA) sponges to modulate gene expression. Nevertheless, their participation in gut microbiota-driven colorectal cance...Circular RNAs (circRNAs) perform critical functions in cancer biology, commonly serving as microRNA (miRNA) sponges to modulate gene expression. Nevertheless, their participation in gut microbiota-driven colorectal cancer (CRC) has yet to be substantially investigated. Fusobacterium nucleatum (F. nucleatum), a well-recognized oncogenic bacterium in the human gut, has been implicated in CRC development, but the underlying mechanisms are not fully defined. In this study, we identified a novel circRNA, circPTBP3, which is the most significantly upregulated circRNA upon F. nucleatum infection, and is significantly upregulated in CRC tissues. CircPTBP3 is preferentially transcribed over its host gene PTBP3 in response to F. nucleatum through activation of the transcription factor ETS1. Functional assays demonstrated that circPTBP3 enhances CRC cell proliferation and tumor growth in vitro and in vivo. Mechanistically, circPTBP3 acts as a molecular sponge for miR-760, thereby relieving its suppression of the downstream target gene PUM1. In clinical CRC specimens, circPTBP3 expression showed a positive correlation with F. nucleatum abundance, PUM1 expression, larger tumor sizes, advanced TNM stages, and a negative correlation with miR-760 levels. These findings establish for the first time that circPTBP3 functions as a pivotal mediator of F. nucleatum 's oncogenicity, and reveal a novel F. nucleatum-circPTBP3-miR-760-PUM1 regulatory axis that promotes CRC progression. CircPTBP3 may serve as a potential biomarker and therapeutic target in F. nucleatum-associated colorectal carcinogenesis.
LIM family proteins play pivotal roles in mechano-transduction, a process often dysregulated in human cancers. However, the functions and mechanisms of LIM proteins in tumor biology remain insufficiently characterized. I...LIM family proteins play pivotal roles in mechano-transduction, a process often dysregulated in human cancers. However, the functions and mechanisms of LIM proteins in tumor biology remain insufficiently characterized. In this study, we demonstrate that the LIM family protein Lipoma Preferred Partner (LPP) is amplified and its expression is upregulated in various human cancer samples, correlating with poor prognosis. We show that LPP is essential for tumor growth and metastasis across multiple tumor models, including xenografts and patient-derived organoids. Mechanistically, mechanical stimulation induces the recruitment of LPP to focal adhesions (FAs) via VASP in tumor cells, promoting Paxillin-dependent FA maturation. Furthermore, LPP inactivates the core kinases of the Hippo pathway, LATS1/2, through PP2A complex-mediated dephosphorylation, thereby leading to the activation of YAP. Collectively, our findings reveal the mechanistic basis of LPP-mediated mechano-transduction and demonstrate how its upregulation drives tumor progression. These insights may have important implications for cancer diagnosis and therapy.
Lung cancer persists as a major contributor to global cancer-related mortality, with metastasis, recurrence, and therapy resistance posing substantial barriers to effective disease management. CDYL has gained recognition...Lung cancer persists as a major contributor to global cancer-related mortality, with metastasis, recurrence, and therapy resistance posing substantial barriers to effective disease management. CDYL has gained recognition as an epigenetic co-repressor involved in multiple dimensions of oncogenesis. However, its precise mechanistic contributions to non-small cell lung cancer (NSCLC) pathogenesis remain inadequately characterized. In this study, we observed pronounced CDYL overexpression in clinical NSCLC specimens, which exhibited a strong association with advanced disease staging and diminished patient survival. Functional profiling established that CDYL augments proliferative and migratory properties of NSCLC cells in vitro, whereas its genetic suppression markedly impaired tumor development in murine xenograft models. Mechanistically, we uncovered the deubiquitinating enzyme OTUB1 as a critical upstream effector that interacts with and stabilizes CDYL, thereby elevating its protein abundance. Further exploration demonstrated that CDYL confers cellular resistance to cuproptosis, a recently delineated copper-induced modality of regulated cell death. Through integrated transcriptomic and epigenomic interrogation, we elucidated that CDYL collaborates with EZH2 to promote H3K27me3 enrichment at the promoter region of the transcription factor SOX18, resulting in its transcriptional repression. Subsequent investigations revealed that SOX18 transcriptionally activates FDX1, a central regulator of cuproptosis. Consequently, CDYL-driven SOX18 repression leads to attenuated FDX1 expression, suppression of cuproptosis, and accelerated tumor progression. Importantly, administration of the copper chelator tetrathiomolybdate (TTM) counteracted the tumor-restraining consequences of CDYL ablation in vivo. Collectively, our findings unveil the OTUB1/CDYL/SOX18/FDX1 signaling cascade as a previously uncharacterized regulatory circuit that facilitates lung cancer progression through cuproptosis inhibition, providing new insights into the epigenetic regulation of cuproptosis and identifying potential therapeutic targets for NSCLC. Proposed molecular mechanism: OTUB1-mediated deubiquitination stabilizes CDYL, which recruits EZH2 to deposit H3K27me3 at the SOX18 promoter, thereby repressing SOX18 expression and subsequent FDX1 transactivation, leading to cuproptosis suppression and lung cancer progression.
Gastric cancer (GC) remains a leading cause of global cancer mortality, necessitating deeper molecular insights. This study identifies KIF15 as a key driver of GC progression through integrated analysis of TCGA data and...Gastric cancer (GC) remains a leading cause of global cancer mortality, necessitating deeper molecular insights. This study identifies KIF15 as a key driver of GC progression through integrated analysis of TCGA data and experimental validation. KIF15 is significantly overexpressed in GC tissues and correlates with advanced tumor stage, metastasis, and poor prognosis. Functional assays demonstrate that KIF15 enhances cancer stem cell (CSC) properties, proliferation, migration, invasion, and cisplatin resistance in GC cells. Mechanistically, KIF15 interacts with peroxiredoxin 1 (PRDX1), stabilizing this antioxidant protein to reduce intracellular hydroperoxides and maintain mitochondrial function. Depletion of PRDX1 reverses KIF15-mediated oncogenic effects. Further investigation reveals Yin Yang 1 (YY1) as the upstream transcriptional activator of KIF15. YY1 directly binds the KIF15 promoter, and its overexpression elevates KIF15 expression. Rescue experiments confirm that YY1 promotes GC malignancy via the KIF15-PRDX1 axis. Crucially, YY1 also transcriptionally regulates PRDX1, forming a coordinated regulatory circuit. In vivo models corroborate that the YY1/KIF15/PRDX1 axis drives tumor growth, metastasis, and chemoresistance. Collectively, these findings establish a novel YY1-KIF15-PRDX1 signaling axis that induces mitochondrial ROS imbalance to facilitate GC progression, offering potential prognostic markers and therapeutic targets.
Cell competition is an evolutionarily conserved quality control mechanism that eliminates less-fit cells to ensure optimal tissue integrity during development, homeostasis, and regeneration. Beyond these physiological ro...Cell competition is an evolutionarily conserved quality control mechanism that eliminates less-fit cells to ensure optimal tissue integrity during development, homeostasis, and regeneration. Beyond these physiological roles, recent evidence implicates a role for cell competition in disease, particularly in cancer, where it can function by either suppressing or promoting malignant progression. In this review, we provide an overview of the different molecular mechanisms that drive cell competition and their impact on cancer development and progression. We will evaluate the current state-of-the-art in vitro experimental systems that can be employed to study these processes. Ranging from classical 2D co-culture systems to advanced organoid and organ-on-chip platforms, these model systems collectively enhance our understanding of the complex cellular interactions that underlie the competitive differences between cells. By integrating insights from diverse model systems, we highlight how cell competition shapes tumor dynamics and discuss how this knowledge could inspire novel therapeutic strategies to prevent or control tumor growth.
Myofibroblastic cancer-associated fibroblasts (myoCAFs) represent a crucial stromal cell subpopulation associated with tumor growth, relapse, and metastasis. In this study, we identify a noncanonical mechanism through wh...Myofibroblastic cancer-associated fibroblasts (myoCAFs) represent a crucial stromal cell subpopulation associated with tumor growth, relapse, and metastasis. In this study, we identify a noncanonical mechanism through which head and neck cancer cells regulate myoCAF activation. Co-culture with tumor organoids promoted the expression of cytokine interaction-related genes and myoCAF phenotypic markers in paracancerous fibroblasts (PFs). Cytokine and tissue array analyses revealed that upregulation of colony-stimulating factor-2 (CSF2) in tumor cells correlated with overexpression of nicotinamide N-methyltransferase (NNMT) in CAFs. Notably, CSF2 treatment enhanced myoCAF properties in a NNMT-dependent manner, while NNMT overexpression remained largely unaffected by transforming growth factor-β (TGF-β). In both assembled organoid and xenograft models, tumor growth was reduced when either CSF2 in cancer cells or CSF2 receptor subunit CSF2RA in CAFs was knocked down. Mechanistically, CSF2 induced FOS phosphorylation at Ser32, promoting nuclear translocation of phosphorylated FOS (p-FOS) to regulate NNMT transcription. In drug screening assays, CSF2 blockade partially overcame resistance to TGF-β inhibition. These findings establish the CSF2/FOS/NNMT axis as a TGF-β-independent pathway driving myoCAF activation.
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic resistance posing a critical barrier to improving patient outcomes. While stress granules (SGs) are implicated in tumor...Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic resistance posing a critical barrier to improving patient outcomes. While stress granules (SGs) are implicated in tumor adaptation, their molecular features, clinical relevance, and mechanistic roles in HCC remain poorly defined. Here, we established a 26-gene SG signature and develop a SG score that robustly stratifies HCC patients, linking high score with aggressive molecular subtypes and poor survival. Moreover, we demonstrate that β-catenin directly binds the promoters of SG genes and activates their transcription. Crucially, we reveal that elevated SG activity correlates sorafenib resistance and identify CAPRIN1 as a key driver of sorafenib resistance through suppression of ferroptosis. Mechanistically, CAPRIN1 interacts with NCOA4 mRNA via its RGG domain and recruits NCOA4 mRNA into SGs, leading to repression of NCOA4 translation and consequent blunting of sorafenib-induced ferroptosis. Genetic disruption of CAPRIN1 restores NCOA4 expression and resensitizes resistant tumors to sorafenib. Our work establishes SG activity as a prognostic biomarker and reveals a druggable SG-ferroptosis axis, offering novel strategies to overcome therapy resistance in HCC.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally; however, the molecular drivers remain unclear. Dysregulated cholesterol metabolism is a hallmark of HCC and contributes to tumor pro...Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally; however, the molecular drivers remain unclear. Dysregulated cholesterol metabolism is a hallmark of HCC and contributes to tumor progression. The Niemann-Pick type C1 protein (NPC1), a lysosomal cholesterol transporter, is overexpressed in cancers; however, its oncogenic mechanisms in HCC remain unclear. In this study, we identified NPC1 as a critical regulator of HCC progression through dual mechanisms involving p53 destabilization and modulation of cholesterol metabolism. Analysis of the clinical data revealed that NPC1 was significantly upregulated in HCC tissues and correlated with poor prognosis. Functional studies have demonstrated that NPC1 silencing suppresses HCC cell proliferation, both in vitro and in vivo. Mechanistically, NPC1 interacts with deubiquitinase ubiquitin-specific protease 7 (USP7), disrupting its binding to p53 and enhancing p53 ubiquitination and proteasomal degradation. Concurrently, NPC1 modulates cholesterol synthesis and distribution via the p53-SREBP2 axis, and p53 knockdown reverses the cholesterol reduction caused by NPC1 silencing. The pharmacological activation of p53 reversed the decrease in cholesterol levels mediated by the overexpression of NPC1. These findings reveal that NPC1 is a multifaceted oncoprotein in HCC, linking cholesterol metabolism to p53 regulation and highlighting its potential as a therapeutic target for HCC intervention.
S-palmitoylation, a reversible lipid-based post-translational modification, is notably elevated in colorectal cancer (CRC) due to common lipid metabolism disorders. It has been reported to play crucial roles in regulatin...S-palmitoylation, a reversible lipid-based post-translational modification, is notably elevated in colorectal cancer (CRC) due to common lipid metabolism disorders. It has been reported to play crucial roles in regulating membrane composition, cell proliferation, and metastasis in various malignancies such as pancreatic and breast cancers. However, its role in the progression of CRC remains poorly understood. ZDHHC9, a member of the palmitoyl transferase family, is significantly upregulated in CRC patients and correlates with poor prognosis. Knockdown of ZDHHC9 impairs CRC cell proliferation and migration both in vitro and in vivo. RNA sequencing revealed that ZDHHC9 depletion markedly downregulates the cAMP signaling pathway. Mechanistically, ZDHHC9 knockdown impairs ADCY4 activity by reducing S-palmitoylation of KLF5 at cysteine 438, thereby modulating the ZDHHC9/KLF5/ADCY4 axis and downstream cAMP/PKA/CREB signaling to influence CRC cell proliferation and migration. Our findings demonstrate that ZDHHC9 promotes CRC progression by regulating intracellular cAMP levels through KLF5 palmitoylation, providing a novel therapeutic perspective targeting palmitoylation in CRC. The mechanism diagram of this study. ZDHHC9 mediates palmitoylation of KLF5 at cysteine 438, thereby enhancing ADCY4 activity and increasing intracellular cAMP levels. This elevation in cAMP promotes PKA and phosphorylation of CREB, ultimately activating the cAMP/PKA/CREB signaling pathway, which contributes to the regulation of CRC cell proliferation, migration, and resistance to 5-FU. (Created with BioRender.com).
Kim JK, Park MG, Ham SW
… +23 more, Yoon S, Kim S, Jang J, Kim H, Hong N, Park JM, Park CG, Park MJ, Choi SH, Kim JY, Jeon HY, Seo S, Lee SY, Lee Y, Cho HJ, Gwak M, Kim EJ, Eun K, Shin YJ, Nam DH, Kim SH, Yoo SJ, Kim H
Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor...Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.
Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes across multiple malignancies, yet resistance to immune checkpoint blockade remains common. Here, we identify HILPDA as a tumor-intrinsic regulator o...Immune checkpoint blockade (ICB) targeting PD-1/PD-L1 improves outcomes across multiple malignancies, yet resistance to immune checkpoint blockade remains common. Here, we identify HILPDA as a tumor-intrinsic regulator of immune evasion in breast cancer. HILPDA overexpression increases the infiltration and suppressive activity of regulatory T cells while decreasing the infiltration, activation, and cytotoxicity of CD8 T cells and natural killer cells, thereby establishing an immunosuppressive tumor microenvironment. Mechanistically, HILPDA binds to HSP90 and protects the transcription factor KLF5 from proteasomal degradation, sustaining fatty acid synthesis and lipid droplet accumulation. The resulting increase in palmitate augments PD-L1 palmitoylation at cysteine 272, enhancing PD-L1 membrane localization and palmitoylation-dependent stability and maintaining inhibitory signaling. We further showed that the E3 ligase TRIM21 mediates K63-linked polyubiquitination of HILPDA and promotes its degradation. In breast cancer models, pharmacologic engagement of TRIM21 with fenretinide decreases PD-L1 palmitoylation, reprograms the tumor microenvironment toward cytotoxic immunity, restores antitumor responses, and improves anti-PD-1 efficacy. Collectively, these results indicate that HILPDA-driven lipogenesis increases PD-L1 palmitoylation, leading to immune evasion and ICB resistance, and TRIM21/HILPDA-targeted combinations are proposed as a therapeutic strategy.
The paper ( https://doi.org/10.1038/s41388-025-03410-3 ) was retracted due to the use of a contaminated cell line; after communication with the original journal's editors, we have obtained permission to replace the cell...The paper ( https://doi.org/10.1038/s41388-025-03410-3 ) was retracted due to the use of a contaminated cell line; after communication with the original journal's editors, we have obtained permission to replace the cell line and resubmit the manuscript. Bladder cancer (BLCa) metastasis is a predominant cause of death for bladder cancer patients. Histone demethylase KDM3A specifically removes the repressive mono- or di-methyl marks from H3K9 and thus contributes to the activation of gene transcription. However, the underlying mechanisms of KDM3A in bladder cancer are poorly understood. Here, we report that high levels of KDM3A are associated with bladder cancer clinical progression. KDM3A silencing inhibits bladder cancer cell growth, cell migration and invasion in vitro and in vivo. Mechanistically, we demonstrate that the deubiquitinase USP13 interacts with KDM3A and specifically removes its K63-linked ubiquitin chains, thereby indirectly promoting K48-linked polyubiquitination-dependent proteasomal degradation of KDM3A. USP13 was significantly down-regulated in bladder cancer tissues and negatively associated with KDM3A expression. Furthermore, we show in bladder injected-liver metastasis xenograft model that USP13 inhibits bladder cancer metastasis through destabilizing cytoplasmic KDM3A. Collectively, our findings identify KDM3A is an important regulator of bladder cancer cell growth and metastasis and targeting USP13/KDM3A complex could be a valuable strategy to ameliorate bladder cancer progression and metastasis.
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticat...Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticated mechanisms for immune evasion, including proinflammatory cytokine secretion and immune cell effector function impairment. Due to these complex immune evasion strategies, immunotherapies are effective in only a minority of GBM patients. Herein, we identified P21-activated kinase 4 (PAK4) as a critical immunosuppressive gene that is highly expressed in GBM and actively promotes tumor progression. Mechanistically, PAK4 mediates transforming growth factor-beta 1 (TGF-β1) release from GBM cells, triggering PI3K/AKT/NF-κB signalling pathway activation in CD8 + T cells, which consequently upregulates phospholipase A2 group IVA (PLA2G4A) expression. PLA2G4A activation triggers phosphatidylcholine (PC) depletion in CD8 + T cells, damages mitochondrial and lysosomal functions, inducing subsequent mitophagic flux suppression, which culminates in the functional exhaustion of CD8 + T cells. Furthermore, PLA2G4A inhibitor treatment effectively reduces CD8 + T cell exhaustion while enhancing T cell cytotoxic capacity. Finally, combined PAK4 inhibitor and anti-PD-L1 therapy increases the CD8 + T cell cytotoxic function and suppresses tumor growth. Overall, our study results suggest that targeting PAK4 could be a potential strategy for GBM immunotherapy.
The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistanc...The introduction of next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide (ENZ), has improved the clinical management of castration-resistant prostate cancer (CRPC). However, acquired resistance to these therapies often develops rapidly, and the underlying resistance mechanisms remain largely unclear. Here, we identified the aryl hydrocarbon receptor (AHR) as a crucial operator of ENZ-resistant CRPC. AHR is upregulated in three ENZ-resistant human CRPC cell lines (C4-2B, CWR-R1, and VCaP) as well as in high-grade prostate tumors from patients receiving ENZ treatment. Stable knockdown of AHR substantially reduced the growth of ENZ-resistant CRPC cells and xenografts. Mechanistically, AHR engages in distinct transcriptional programs in a cellular context-dependent manner. AHR directly regulates the transcription and expression of androgen receptor (AR)/glucocorticoid receptor (GR) co-target genes in CWR-R1 cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2B cells, indicating an AR-indifferent mechanism of ENZ resistance. The diverse mechanisms triggered by ENZ were also manifested in clinical samples. Collectively, these findings characterize AHR's contribution to ENZ resistance in CRPC and illuminate the potential of targeting AHR for treating ARSI-resistant advanced prostate cancer.
Alterations in metabolism are recognised as a hallmark of cancer, allowing for rapid proliferation in an environment often hypoxic and short of nutrients. Cells within the tumour microenvironment (TME) often undergo meta...Alterations in metabolism are recognised as a hallmark of cancer, allowing for rapid proliferation in an environment often hypoxic and short of nutrients. Cells within the tumour microenvironment (TME) often undergo metabolic alterations to adapt to these conditions, and this can also contribute to tumour progression. Cancer associated fibroblasts (CAFs) are amongst the most abundant non-cancerous cells in the TME and the main cells responsible for production and maintenance of the extracellular matrix. However, CAF subtypes can impact tumours in different ways and have been shown to play a role in alterations to lipid metabolism within tumours, being able to produce and secrete lipids, internalise them from the surrounding environment, and undergo fatty acid oxidation. Whilst this is still an emerging area of research, it appears that CAFs can have opposing roles in lipid metabolism in different types of cancer. Understanding the different metabolic pathways utilised in both CAFs and cancer cells and how external factors such as obesity and high fat diets influence them, could provide novel treatment avenues in the future. This review explores the literature surrounding lipid metabolism in CAFs and how this influences tumour progression and treatment resistance.
Cancer cells exhibit abnormally altered proteome to satisfy the metabolic demands that arise from heightened proliferation. Trypsin-like serine proteases are a class of proteolytic enzymes whose expression is often dysre...Cancer cells exhibit abnormally altered proteome to satisfy the metabolic demands that arise from heightened proliferation. Trypsin-like serine proteases are a class of proteolytic enzymes whose expression is often dysregulated in cancer. Serine protease 22 (PRSS22) has been associated with the tumorigenesis of several types of cancers. In this study, we identified PRSS22 as a key driver of inflammation-cancer transition (ICT) in colorectal cancer (CRC). PRSS22 expression was positively correlated with the pathological progression of colitis-associated ICT. Genetic disabling of PRSS22 inhibited the growth and migration of and caused redox stress in CRC cells. Mechanistically, knocking down PRSS22 promoted the expression of HMOX1, which fine-tuned the inflammatory response and led to ferroptosis. Loss of PRSS22 also prevented the cleavage of osteopontin and reduced the migratory capacity of CRC cells. We also observed a reduction of M0-to-M2 macrophage polarization in a co-culture system of CRC cells and THP-1-derived macrophages. Altogether, this study reveals a tumor-promoting function of PRSS22 and positions it as a key driver of CRC progression. Targeting PRSS22 represents a promising therapeutic strategy against CRC.
Ferroptosis is a form of iron-dependent programmed cell death (PCD) that, once activated, inhibits tumor progression. However, the specific mechanisms influencing ferroptosis in nasopharyngeal carcinoma (NPC) are limited...Ferroptosis is a form of iron-dependent programmed cell death (PCD) that, once activated, inhibits tumor progression. However, the specific mechanisms influencing ferroptosis in nasopharyngeal carcinoma (NPC) are limited and warrant further investigation. This study proposes that MICAL2 not only influences the nuclear translocation of p53 but also facilitates the ubiquitination of p53 by recruiting the E3 ubiquitination ligase MDM2, leading to its degradation. This process inhibits ferroptosis in NPC cells, thereby promoting NPC progression and adversely affecting the prognosis of NPC patients. Additionally, we identified a novel long non-coding RNA (lncRNA), LINC-AC092535.5, which directly modulates the MICAL2 mRNA level through dual reinforcement at both transcriptional and post-transcriptional levels. Transcriptome sequencing and RACE experiments provided insights into the function of this new lncRNA. These findings will contribute to the expansion of the ferroptosis gene regulatory network and inform new clinical treatment strategies for NPC.
Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, w...Proteasome inhibitor (PI) resistance remains a major barrier in the treatment of multiple myeloma (MM), underscoring the urgent need to elucidate underlying mechanisms and identify actionable therapeutic targets. Here, we uncover METTL16 as a regulator of MM progression and PI sensitivity via an m6A methyltransferase activity-independent mechanism of translational control. Mechanistically, METTL16 overexpression is associated with altered PERK-eIF2α interaction and reduced eIF2α phosphorylation, accompanied by increased translation of key transcripts, including PSMB5 and CCND1. Consistently, these translational outputs coincide with increased proteasome activity and proliferative capacity. Notably, pharmacological targeting of METTL16 enhances the efficacy of multiple PIs in MM cells. These findings not only expand the functional landscape of METTL16 beyond RNA methylation, but also suggest that METTL16 represents a potential target for improving PI-based therapy in MM.
Guchhait K, Yoon HS, An HS
… +14 more, Shin S, Nam HS, Yanqui-Rivera FD, Oña SM, Mendez MÁ, Hwang JY, Park D, Park CS, Han JY, Chung DY, Park S, Kim EK, Yang SG, Cho SK
Metastasis is the primary cause of mortality in advanced prostate cancer, and the emergence of resistance to androgen receptor (AR)-targeted therapies highlights the urgent need for alternative therapeutic strategies. Me...Metastasis is the primary cause of mortality in advanced prostate cancer, and the emergence of resistance to androgen receptor (AR)-targeted therapies highlights the urgent need for alternative therapeutic strategies. Metabolic reprogramming has increasingly been recognized as a key driver of metastatic progression. In this study, we uncover a novel tumor-suppressive role for cereblon (CRBN), a substrate receptor of the CRL4 E3 ubiquitin ligase complex, in modulating prostate cancer metastasis through regulation of 6-phosphogluconate dehydrogenase (6PGD), a critical enzyme in the oxidative pentose phosphate pathway (oxPPP). CRBN directly binds a conserved C-terminal α-helix in 6PGD, promoting its polyubiquitination and proteasomal degradation independently of immunomodulatory drugs (IMiDs). Genetic or pharmacological loss of CRBN via CRISPR/Cas9, RNA interference, or PROTAC-mediated degradation stabilized 6PGD and elevated the NADPH/NADP ratio. Conversely, re-expression of wild-type CRBN reduced 6PGD levels, restored NADPH/NADP ratio, and suppressed cell migration and invasion. Transcriptomic profiling revealed CRBN-induced upregulation of CDH1 and downregulation of the EMT marker MMP1, while CRBN degradation produced the opposite pattern-both effects were reversed by 6PGD inhibition. These regulatory effects were conserved across multiple cancer cell lines and observed in CRBN-deficient mouse tissues. Functional studies using intra-splenic xenograft models further demonstrated that CRBN suppresses metastatic dissemination. Collectively, our findings identify 6PGD as a novel endogenous substrate of CRBN and establish the CRBN-6PGD axis as a critical metabolic checkpoint in prostate cancer metastasis. Therapeutic targeting of this pathway may offer promising strategies for CRBN-deficient or 6PGD-driven cancers.