Levels of pancreatic ductal adenocarcinoma (PDAC) are increasing, with epidemiological studies nominating obesity, altered cholesterol metabolism, and elevated lipids as risk factors. In prior studies, we determined that...Levels of pancreatic ductal adenocarcinoma (PDAC) are increasing, with epidemiological studies nominating obesity, altered cholesterol metabolism, and elevated lipids as risk factors. In prior studies, we determined that elevated expression of sterol regulatory element binding protein 2 (SREBP2), a transcription factor directing lipid biosynthesis, promoted epithelial-mesenchymal transition and aggressive tumorigenesis in the KPC (LSL-Kras;Trp53;Pdx1-Cre) mouse model of PDAC. We analyzed the consequences of deleting SCAP, a scaffolding protein required for SREBP activation, in KPC mice. Unexpectedly tumorigenesis in KPCS mice was significantly accelerated, with a preponderance of sarcomatoid carcinomas. To better understand SCAP action, we analyzed loss of pancreatic SCAP in isolation in Scap (Pdx1-Cre;Scap) mice. Pancreata of Scap mice had rapid progressive loss of acinar cells, acinar-ductal metaplasia (ADM), infiltration of adipose cells, increased fibrosis, and infiltration of immune cells, indicative of chronic pancreatitis. Single cell RNA sequencing indicated that loss of SCAP suppressed SREBP-dependent transcriptional programs in endocrine and exocrine precursors, but was associated with enhanced SREBP2 activity in fibroblastic populations, compatible with formation of a pro-tumorigenic tumor microenvironment. Together, these results implicate lipid metabolism via SCAP-SREBP signaling as an important metabolic regulator of acinar-ductal differentiation and pancreatic carcinogenesis.
Liver metastasis is a major cause of mortality in gastric cancer (GC), yet the underlying molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression an...Liver metastasis is a major cause of mortality in gastric cancer (GC), yet the underlying molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and cancer progression, but their roles in GC liver metastasis are not fully defined. In this study, lncRNA sequencing of primary GC tumors and matched liver metastatic tissues identified PSPC1-AS2 as significantly upregulated. Its elevated expression was further validated across multiple patient cohorts and public datasets. Functional assays demonstrated that PSPC1-AS2 promotes GC cell migration, invasion, and liver metastasis both in vitro and in vivo. Mechanistically, PSPC1-AS2 is predominantly localized in the nucleus and enhances the mRNA stability of its neighboring gene PSPC1 by recruiting the RNA-binding protein EIF4A3. The PSPC1-AS2/PSPC1 axis facilitates tumor progression and induces macrophage polarization toward the pro-tumorigenic M2 phenotype via increased CCL2 secretion. At the molecular level, PSPC1 interacts with PARP1, competitively inhibiting PARP1-mediated PARylation and dephosphorylation of STAT3, thereby sustaining STAT3 activation and promoting CCL2 transcription. Notably, neutralization of CCL2 effectively reverses PSPC1-induced M2 macrophage polarization. Collectively, these findings reveal a novel PSPC1-AS2/PSPC1/STAT3/CCL2 regulatory axis that drives GC progression and liver metastasis through remodeling of the tumor microenvironment, highlighting a potential therapeutic target for advanced gastric cancer.
Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer, the most common subtype, shows a low pathological complete response (pCR) rate and limited benefit from immunoth...Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer, the most common subtype, shows a low pathological complete response (pCR) rate and limited benefit from immunotherapy, highlighting the need for more effective strategies. Although immunotherapy has become increasingly important in cancer treatment, its efficacy in this subtype remains modest. CDK4/6 inhibitors, first-line treatments for advanced HR + /HER2- breast cancer, not only suppress tumor proliferation but may also reshape the immune microenvironment, offering new opportunities for immunotherapy. In this study, multiplex immunohistochemistry, drug testing of HR + /HER2- breast cancer organoids, single-cell sequencing, and primary cell coculture showed that the CDK4/6 inhibitor palbociclib promotes fibroblast senescence, thereby increasing IGF1 and FGF7 levels. These factors drive macrophage polarization toward an M2-like phenotype through STAT3 Tyr705 phosphorylation and ARG1 upregulation, resulting in arginine depletion and reduced lymphocyte viability. To counteract this immunosuppressive microenvironment, we selected the CSF1R inhibitor pexidartinib. Pexidartinib inhibited macrophage activity, suppressed STAT3 phosphorylation, reduced ARG1 expression, and increased lymphocyte viability, thereby enhancing the antitumor efficacy of palbociclib in HR + /HER2- breast cancer. These findings reveal a previously unrecognized immunosuppressive mechanism induced by CDK4/6 inhibition and support CSF1R blockade as a promising combination strategy.
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation, migration, and apoptosis. It is generally accepted that TGF-β induces cellular responses through Smad...Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates cell proliferation, differentiation, migration, and apoptosis. It is generally accepted that TGF-β induces cellular responses through Smad-dependent gene transcription. However, the underlying mechanisms that modulate the transcriptional activities of Smads are not yet fully understood. Here, we identify BRD2, a member of the bromodomain and extraterminal (BET) family, as a key transcriptional coactivator for Smad3. BRD2 physically interacts with Smad3 through a newly identified Smad3-binding region (SBR). This BRD2-Smad interaction enhances Smad's association with chromatin and amplifies its transcriptional activity, playing a vital role in TGF-β transcriptional and tumor-suppressive responses. Our findings establish BRD2 as an important modulator of TGF-β signaling and suggest that it may serve as a potential target for TGF-β-related diseases.
Lv X, Han L, Tong WW
… +17 more, Sun X, Xu S, Yan Y, Zhou S, Zhang Y, Zhang D, Wang J, Liu J, Zhao H, Yao W, Xiao R, Wang Q, Xu J, Gong L, Wei M, Chen B, He M
PKM serves as a rate-limiting enzyme in glycolysis, which produces two isoforms depending on the inclusion of either exon 9 (PKM1) or exon 10 (PKM2). The M2 pyruvate kinase (PKM2) isoform is commonly upregulated in vario...PKM serves as a rate-limiting enzyme in glycolysis, which produces two isoforms depending on the inclusion of either exon 9 (PKM1) or exon 10 (PKM2). The M2 pyruvate kinase (PKM2) isoform is commonly upregulated in various cancers, where it plays a pivotal role in regulating Warburg effect. Breast cancer stem cells (BCSCs) exhibit enhanced glycolysis, which is crucial for their self-renewal. However, the specific role of PKM2 in BCSCs remains largely unexplored. Here, we report that PKM2 expression is upregulated in BCSCs. Meanwhile, we identify that LINC00887 is significantly upregulated in BRCA through a genome-wide LNCRNA microarray. Moreover, we recognize that hnRNPA1 interacts with PKM pre-mRNA and regulates its mutually exclusive splicing. Furthermore, we demonstrate that LINC00887 maintains the self-renewal of BCSCs by promoting PKM2 splicing and reprogramming glucose metabolism. Mechanistically, LINC00887 upregulates PKM2 expression by binding hnRNPA1, thereby concealing its ubiquitination site, which blocks its ubiquitination and maintains its stability. Consistently, overexpression of hnRNPA1 almost completely rescues/reverses the inhibitory effects of LINC00887 KD in BRCA. Collectively, our study characterizes the LINC00887/hnRNPA1/PKM1/2 axis in BRCA and reveals the essential role of LINC00887 in BCSCs self-renewal/maintenance through promoting hnRNPA1-mediated PKM2 splicing, highlighting the therapeutic potential of targeting cancer metabolism.
Hepatocellular carcinoma (HCC), the most common subtype of primary liver cancer, is characterized by a poor prognosis, with most patients diagnosed at advanced stages that are unresectable and resistant to targeted thera...Hepatocellular carcinoma (HCC), the most common subtype of primary liver cancer, is characterized by a poor prognosis, with most patients diagnosed at advanced stages that are unresectable and resistant to targeted therapies. This underscores the critical need for novel therapeutic targets. In this study, we investigated the role of glutamate-oxaloacetate transaminase 1 (GOT1) in HCC progression and evaluated its therapeutic potential. GOT1 expression was markedly downregulated in HCC tissues compared with adjacent non-tumor tissues, and higher GOT1 expression correlated with improved patient survival. Functional experiments revealed that overexpression of GOT1 suppressed HCC cell proliferation and tumor growth while promoting apoptosis both in vitro and in vivo. Mechanistically, integrated transcriptome sequencing and mass spectrometry identified solute carrier family 25 member 5 (SLC25A5) as a GOT1-interacting partner. GOT1-induced oxidative stress, mitochondrial membrane depolarization, and activation of the apoptotic cascade were mediated through upregulation of SLC25A5; Conversely, SLC25A5 knockdown rescued these phenotypic effects. Importantly, adeno-associated virus-mediated delivery of GOT1 (AAV-TBG-GOT1) significantly inhibited tumor growth in preclinical HCC models, underscoring its translational relevance. Collectively, these results establish GOT1 as a tumor suppressor in HCC that acts via SLC25A5-dependent mitochondrial apoptosis and propose GOT1 as a promising prognostic indicator and therapeutic target for HCC.
Transforming growth factor-β (TGFβ) receptor ALK5 inhibition has shown promise in pancreatic ductal adenocarcinoma (PDAC), but predictive biomarkers remain undefined. We identify angiogenin (ANG) as a negative prognostic...Transforming growth factor-β (TGFβ) receptor ALK5 inhibition has shown promise in pancreatic ductal adenocarcinoma (PDAC), but predictive biomarkers remain undefined. We identify angiogenin (ANG) as a negative prognostic yet positive predictive biomarker for ALK5 inhibition combined with chemotherapy. In the randomized phase II H9H-MC-JBAJ trial, high baseline ANG predicted poor survival with gemcitabine alone but significant benefit from galunisertib addition. Mechanistic studies revealed that tumor-derived ANG binds epidermal growth factor receptor (EGFR) on tumor-associated macrophages (TAMs), activating RhoA-dependent cytoskeletal remodeling and autocrine ALK5/TGFβ signaling. This drives M2-like polarization and Smad2-mediated transcription of tumor necrosis factor-α (Tnf-α), which activates Nf-κB in neighboring tumor cells, conferring chemoresistance. ALK5 inhibition suppressed TAM-derived Tnf-α, reduced M2 polarization, prevented Nf-κB activation, and restored chemosensitivity in ANG-high models. Clinically, elevated ANG correlated with systemic TNF-α, and galunisertib reduced TNF-α exclusively in ANG-high patients, with reductions associated with markedly improved survival. These findings define an ANG-EGFR-TGFβ-TNF-α axis in TAMs as a stromal driver of PDAC chemoresistance, and provide a mechanistic rationale for the development of combination strategies targeting ALK5 signaling in ANG-high PDAC patients.
Metabolic reprogramming is a hallmark of tumorigenesis and progression in hepatocellular carcinoma (HCC) and has emerged as a promising therapeutic strategy. Forkhead box O3 (FOXO3), a critical nuclear transcription fact...Metabolic reprogramming is a hallmark of tumorigenesis and progression in hepatocellular carcinoma (HCC) and has emerged as a promising therapeutic strategy. Forkhead box O3 (FOXO3), a critical nuclear transcription factor, is dysregulated in multiple cancers; however, its precise role in HCC progression remains unclear. In this study, we demonstrate that enhanced glycolysis and glutaminolysis are pivotal metabolic features of HCC, with tumor cells heavily relying on both pathways for survival and proliferation. We identify FOXO3 as a tumor suppressor in HCC that inhibits key metabolic enzymes and metabolites involved in these pathways. This inhibitory effect is mediated through suppression of yes-associated protein (YAP). Mechanistically, FOXO3 directly binds to the GTGAACAT motif (-1824 to -1817) within the YAP promoter, leading to transcription repression of YAP and subsequent disruption of YAP-driven metabolic programs. Pharmacological activation of FOXO3 using specific inducers markedly reduced YAP expression, resulting in inhibition of glycolysis, glutaminolysis, and proliferation in HCC cells. In vivo, activation of the FOXO3/YAP axis effectively suppressed HCC progression through the coordinated inhibition of glycolysis and glutaminolysis. Moreover, FOXO3 inducers significantly impaired the growth and viability of patient-derived HCC organoid models. Hence, these findings identify FOXO3 as a key regulator of metabolic reprogramming in HCC and establish the FOXO3/YAP axis as a promising therapeutic target, suggesting potential strategies for metabolic-based interventions in HCC treatment.
Despite significant advances in colorectal cancer (CRC) diagnosis and treatment, drug therapy of CRC patients is still confronted with considerable challenges. Carbohydrate response element-binding protein (ChREBP), a gl...Despite significant advances in colorectal cancer (CRC) diagnosis and treatment, drug therapy of CRC patients is still confronted with considerable challenges. Carbohydrate response element-binding protein (ChREBP), a glucose-responsive transcription factor regulating glycolysis and de novo lipogenesis, shows elevated expression in human CRC tissues and correlates with poor disease-free survival and overall survival. However, the in vivo role and mechanism of ChREBP in colorectal carcinogenesis remain unclear. We used ChREBP knockout mice, which were intraperitoneally injected with azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in drinking water. In the AOM/DSS-induced colorectal cancer model, carcinogenesis was reduced in ChREBP null mice. In the initial phases of colorectal carcinogenesis, ChREBP deficiency was associated with diminished epithelial cell proliferation and a lower number of aberrant crypt foci, but it had no impact on DNA damage or the severity of colitis. The key transcription factor β-catenin and Wnt target gene expression were both decreased in the colons of ChREBP null mice and in ChREBP-knockdown Caco-2 colorectal cancer cells. In vitro studies demonstrated that ChREBP overexpression promoted β-catenin accumulation, nuclear translocation, and transcriptional activity by interacting with β-catenin, while ChREBP knockdown produced the opposite effects. These findings establish a novel mechanism whereby ChREBP drives CRC progression through Wnt/β-catenin pathway activation, positioning it as both a potential therapeutic target and prognostic biomarker for CRC. Working model of ChREBP in promoting Wnt signaling and colorectal carcinogenesis. [Figure created with BioRender.com ].
Lung cancer is the leading cause of cancer-related deaths in the United States, and ~50% of these patients present with metastatic disease at diagnosis. Epithelial-to-Mesenchymal Transition (EMT) is an important initiati...Lung cancer is the leading cause of cancer-related deaths in the United States, and ~50% of these patients present with metastatic disease at diagnosis. Epithelial-to-Mesenchymal Transition (EMT) is an important initiating step in the metastatic cascade that allows cells to acquire the migratory and invasive phenotypes necessary for dissemination. The transcriptional reprogramming that takes place during EMT has been well described in multiple cancer types; however, the posttranslational regulatory mechanisms that govern EMT are poorly understood. Protein Phosphatase 2 A (PP2A) is serine/threonine (ser/thr) phosphatase that accounts for 50% of cellular ser/thr phosphatase activity and is critically important in regulating signaling homeostasis. PP2A dysregulation has been implicated in cell state regulation, EMT, and metastasis, but the roles of individual PP2A complexes are poorly understood. Our data indicate that suppression of the specific PP2A complex, PP2A-B56α, results in decreased expression of epithelial markers and increased expression of mesenchymal markers consistent with EMT. These molecular changes are associated with migratory and invasive phenotypes both in vitro and in vivo. Furthermore, these migratory phenotypes can be rescued with B56α overexpression. Together, these findings implicate B56α as a key regulator of cellular plasticity and highlight the dynamic nature by which PP2A-B56α posttranslationally regulates NSCLC EMT.
Jeong E, Kim HL, Park S
… +16 more, Jang S, Ku J, Kim H, Kim H, Choi SL, Lee KP, Baek S, Yang JY, Park JH, Yeo J, Lee JJ, Lee SY, Kim SH, Kim HS, Yoon CW, Lee SH
HECT and RCC1-like domain-containing protein 1 (HERC1), a large E3 ubiquitin ligase, has been implicated in neural development and genome stability, but its role in cancer remains unclear. This study identifies HERC1 as...HECT and RCC1-like domain-containing protein 1 (HERC1), a large E3 ubiquitin ligase, has been implicated in neural development and genome stability, but its role in cancer remains unclear. This study identifies HERC1 as a critical regulator of cancer stemness, metastasis, and chemoresistance in head and neck squamous cell carcinoma (HNSCC). CD44⁺ HNSCC organoids with shRNA-mediated HERC1 knockdown were assessed for stemness, EMT, and IL-6/STAT3/HERC1 signaling using molecular assays, CAF co-culture, xenografts, and tissue immunohistochemistry. High HERC1 expression in TCGA-HNSCC datasets was associated with enrichment of stemness signatures. HERC1 knockdown in CD44⁺ cells reduced Sox2, and Slug expression, suppressed EMT, and impaired metastatic potential in Transwell assays and in vivo models. CD44⁺ cells formed organoids in a HERC1-dependent manner. CAF co-culture showed that IL-6 promoted organoid invasiveness through STAT3 activation and HERC1 upregulation. Mechanistic validation revealed that HERC1 modulation altered p-STAT3, p-ERK, CD44, and Slug levels, and STAT3 inhibition reduced HERC1 expression, defining a p-STAT3-HERC1-p-ERK axis. IL-6 neutralization or HERC1 inhibition sensitized organoids to 5-fluorouracil and cisplatin, and combined HERC1 knockdown with 5-FU markedly reduced tumor growth and increased apoptosis. Tissue arrays confirmed elevated HERC1 and pathway markers in advanced HNSCC. These findings define an p-STAT3-HERC1-p-ERK signaling axis that promotes cancer stemness and chemoresistance through CD44 tumor-stromal crosstalk. Targeting HERC1 may offer a promising strategy to eliminate cancer stem-like cells in HNSCC.
K-Ras represents one of the most frequently mutated and therapeutically relevant oncogenic drivers. Clinical and epidemiological data suggest association between specific KRAS alleles, therapeutic responses, and patient...K-Ras represents one of the most frequently mutated and therapeutically relevant oncogenic drivers. Clinical and epidemiological data suggest association between specific KRAS alleles, therapeutic responses, and patient outcomes, however, direct experimental validation of these relationships has been limited. In this study, we investigate the differential impacts of three most common K-Ras G12 mutants (K-Ras, K-Ras, and K-Ras) in the colon using in vivo models. Although tumors harboring different Gly12 mutants exhibited no obvious histological differences, their effects on survival outcomes and therapeutic responses displayed pronounced allele specific differences. Transcriptomic analyses revealed an allele-agnostic signature enriched for gene sets associated with MAPK signaling, receptor tyrosine kinase pathways, and immune-modulating pathways, relative to K-Ras WT tumors. In contrast, the allele-specific signature revealed marked enrichment of Notch and Wnt/β-catenin signaling pathways in K-Ras tumors. Pharmacological inhibition of these pathways, in combination with a K-Ras inhibitor, led to either addictive or synergistic reduction in tumor cell viability, in an allele-specific manner. These findings highlight the distinct biological consequences of individual K-Ras G12 mutations in colonic tumorigenesis and underscore therapeutic relevance of allele-specific signaling dependencies, offering a foundation for the development of effective, allele-informed therapeutic strategies for K-Ras mutant cancers.
The Wnt (Wingless/Integrated) signaling pathway is a highly conserved regulator of development, stem cell maintenance, and tissue homeostasis. Its dysregulation is a hallmark of cancer, driving uncontrolled proliferation...The Wnt (Wingless/Integrated) signaling pathway is a highly conserved regulator of development, stem cell maintenance, and tissue homeostasis. Its dysregulation is a hallmark of cancer, driving uncontrolled proliferation, epithelial-mesenchymal transition, invasion, and therapy resistance. Increasing evidence shows that Wnt signaling in tumor cells does not operate in isolation but is dynamically shaped by reciprocal interactions with the tumor microenvironment (TME), including fibroblasts, immune and endothelial cells, extracellular matrix, and metabolic stressors. These bidirectional circuits sustain cancer stemness, remodel stromal architecture, and create immunosuppressive and pro-angiogenic conditions that foster tumor growth as well as metastatic dissemination and colonization. In this review, we examine how canonical and non-canonical Wnt pathways intersect with the TME across distinct stages of the metastatic cascade, from local invasion to the establishment of distant niches. We further evaluate therapeutic approaches targeting Wnt signaling and discuss their potential to overcome immune evasion and metastatic progression when combined with immunotherapy or stromal-targeted agents. Finally, we highlight emerging preclinical models, including organoids and tumor-on-a-chip systems, that are advancing our understanding of Wnt-TME crosstalk. Together, these insights position Wnt signaling as a central orchestrator of cancer progression and metastasis and a promising therapeutic target for improving outcomes in advanced cancer.
Cancer-associated hyperfibrinolysis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Plasmin is the key enzyme of fibrinolytic system...Cancer-associated hyperfibrinolysis are potentially fatal outcomes of advanced cancer. Unfortunately, this knowledge has not yet led to any breakthrough in cancer therapy. Plasmin is the key enzyme of fibrinolytic system. The identification of a direct link between plasmin and the tumor progression remains unknown. Here, we demonstrated that plasmin expression was significantly upregulated in HCC tissue, especially tumor tissues from patients who had received chemotherapy. Through in vitro and in vivo models, we showed that plasmin enhanced HCC cell invasion and migration. Pharmacological inhibition of plasmin with tranexamic acid (TXA) suppressed tumor invasion and metastasis. Mechanistically, we identified plasmin could directly bind to CXCR4, which potentiated the CXCL12/CXCR4 interaction and activated the PI3K/AKT/mTOR signaling pathway. Moreover, CDDP-resistant cells had higher expression of plasmin and stronger invasion and metastasis ability, which were effectively suppressed by plasmin inhibitor, and combining TXA with CDDP synergistically inhibited tumor progression and metastasis in mouse model and human HCC organoids. Our findings reveal a novel plasmin-CXCR4 axis driving HCC dissemination and suggest that targeting plasmin may enhance the efficacy of conventional chemotherapy.
Cancer remains a leading cause of human mortality worldwide, imposing a substantial public health burden. A deep understanding of the tumor microenvironment (TME) is essential for improving cancer care. Erythroid progeni...Cancer remains a leading cause of human mortality worldwide, imposing a substantial public health burden. A deep understanding of the tumor microenvironment (TME) is essential for improving cancer care. Erythroid progenitor cells (EPCs) were traditionally viewed solely as intermediates in erythropoiesis; however, growing evidence indicates their active involvement in cancer progression and immune evasion. Research on EPCs increasingly utilizes omics sequencing technologies. Multi-omics strategies in particular enable in-depth investigation of the functional mechanisms of EPCs and their interactions with tumor and immune cells. This review examines various omics methodologies applied to EPCs from an oncology perspective, including transcriptomics, proteomics, epigenomics, and metabolomics, while critically assessing the advantages and limitations of each approach. Furthermore, it synthesizes how the integration of multiple omics technologies provides a more comprehensive view of EPC biology, particularly through complementary data modalities. This review also discusses artificial intelligence (AI)-powered multi-omics integration strategies and explore the translational potential of EPC-focused research in advancing cancer therapeutics from bench to bedside.
Protein post-translational modifications are crucial in driving cancer development and progression. The SUMO E3 ligase PIAS4 regulates various cellular processes, thereby promoting tumour advancement. However, the role o...Protein post-translational modifications are crucial in driving cancer development and progression. The SUMO E3 ligase PIAS4 regulates various cellular processes, thereby promoting tumour advancement. However, the role of PIAS4 in breast cancer remains unclear. This study aimed to examine the protein levels of PIAS4 in clinical specimens, explore PIAS4 regulates cell cycle mechanism and investigate the synergistic inhibitory effects of PIAS4 and CDK6 inhibition on breast cancer progression. Our findings revealed that PIAS4 was highly expressed in breast cancer and negatively correlated with prognosis. Abrogation of PIAS4 inhibited breast cancer cell proliferation and induced G1 phase cell cycle delay. The primary mechanism involved PIAS4-mediated SUMOylation of CDK6, which enhanced retinoblastoma 1 (RB1) phosphorylation and the transcription of downstream cell cycle genes, facilitating cell cycle G1 phase progression. We found that CDK6 underwent SUMO1 and SUMO2/3 modifications and identified the main SUMO2/3 modification sites. Mutations at these sites inhibit CDK6-mediated RB1 phosphorylation, consequently blocking cell cycle progression in the G1 phase. CDK6 kinase activity is reduced following PIAS4 knockdown, which may be associated with decreased binding of Cyclin D1 to CDK6. Moreover, in mouse xenograft models, combining PIAS4 and CDK6 inhibition enhanced therapeutic efficacy against breast cancer. Therefore, targeting PIAS4 to impede cell cycle progression may be a novel strategy for breast cancer treatment.
The clinical application of targeted therapy and immune checkpoint inhibitors (ICIs) has significantly improved the survival prognosis of patients with hepatocellular carcinoma (HCC). However, due to the high heterogenei...The clinical application of targeted therapy and immune checkpoint inhibitors (ICIs) has significantly improved the survival prognosis of patients with hepatocellular carcinoma (HCC). However, due to the high heterogeneity of HCC, the response rate to immunotherapy is still low, and there is an urgent need to identify reliable biomarkers and potential therapeutic targets to improve the therapeutic benefit. In this study, a patient-derived xenograft (PDX) model of HCC was constructed to compare and analyze the tumor tissues of the immunotherapy responder group and the non-responder group. RNA sequencing and proteomics combined analysis found that histone H3K9 trimethyltransferase SETDB2 was highly expressed in the non-responder group. Functional experiments showed that SETDB2 deficiency could significantly inhibit tumorigenesis, enhance CD8⁺ T cell infiltration, and improve the immune microenvironment. Further mechanistic studies found that SETDB2 shut down the chromatin structure of the promoter region of the splicing factor SRSF1 through H3K9me3 modification, inhibiting its expression, thereby leading to a decrease in the proportion of functional spliceosomes of the immune regulatory factor SHP-1. After the activity of SHP-1 was weakened, the JAK/STAT3 signaling pathway was continuously activated, leading to an enhanced tumor immunosuppressive phenotype. SETDB2 overexpression also promoted the polarization of tumor-associated macrophages M2 and inhibited the function of effector T cells, leading to a decrease in immunotherapy response. This study systematically revealed that SETDB2 regulates SRSF1 expression through an epigenetic mechanism mediated by H3K9me3, thereby driving the SHP-1 spliceosome deviation, activating STAT3 signaling and reshaping the key pathway of the immune microenvironment. The SETDB2/SRSF1/SHP-1/STAT3 axis plays a core role in HCC immune escape, providing a new perspective on the mechanism of resistance to immunotherapy in liver cancer, and providing a theoretical basis and potential biomarkers for the combined epigenetic targeted intervention strategy of ICIs.
Prostate cancer is the most common malignant tumor among men worldwide, severely threatening the health of aging males. RNA 5-methylcytosine (m5C) modification has been demonstrated to play a significant role in the init...Prostate cancer is the most common malignant tumor among men worldwide, severely threatening the health of aging males. RNA 5-methylcytosine (m5C) modification has been demonstrated to play a significant role in the initiation and progression of various tumors. However, the role of ALYREF, a key methyl-recognizing protein for m5c modification, is still unclear in prostate cancer. In our study, we found that knockdown of ALYREF reduces the proliferation, invasion and metastasis of prostate cancer. ALYREF promotes anoikis resistance in prostate cancer by positively regulating BPIP3 and thereby activating autophagy. Mechanistically, we found that ALYREF is a methylation recognition protein that directly and specifically recognizes the m5c site of BNIP3 mRNA and enhances the stability of BNIP3 mRNA, which activates autophagy in prostate cancer cells, and thus enhances the anoikis resistance and metastatic ability of cancer cells. Overall, our study revealed the important role of ALYREF-mediated m5C methylation modification in the mechanisms of autophagy and anoikis resistance in prostate cancer, providing an important molecular target for the treatment of advanced prostate cancer.