Oncogene最新文献

Mesothelioma is an aggressive cancer that is often characterized by loss of the BRCA1-associated protein 1 (BAP1) tumor suppressor gene. This alteration typically occurs as an early clonal event in mesothelioma development, making it a promising candidate for both diagnostic and therapeutic applications. Functionally, BAP1 regulates gene expression through interactions with Polycomb-group complexes, and it plays roles in various other cellular processes including DNA repair, replication stress, and cell metabolism. While preclinical research has identified multiple potential vulnerabilities in BAP1-deficient tumors-including sensitivity to EZH2-, HDAC-, PARP-, and FGFR-inhibitors-translating these findings to the clinic remains a challenge. In this review, we provide a comprehensive overview of BAP1's molecular functions in mesothelioma, with a focus on their translation into clinical therapeutics for this hard-to-treat malignancy.

Enhancer of Zeste Homolog 2 (EZH2) is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2). It catalyzes H3K27 methylation for epigenetic silencing of tumor suppressors and critically drives prostate cancer (PCa) progression. However, inhibitors of EZH2 catalytic function (EZH2i), such as EPZ-6438, showed limited efficacy in PCa. Here, we designed and developed a series of VHL-based proteolysis-targeting chimera (PROTAC) degraders of EZH2 using EPZ-6438 as a ligand and identified PROTAC-6272 as a lead compound. PROTAC-6272 effectively degraded EZH2 and other PRC2 subunits across diverse PCa cell lines. However, PROTAC-6272 and other similar EZH2i-based PROTACs were consistently unable to decrease androgen receptor (AR), a gene that is directly activated by solo EZH2. Mechanistically, EZH2 PROTACs failed to degrade EZH2 coactivators, such as p300, due to their inability to engage EZH2 outside of the PRC2 complex. Nevertheless, PROTAC-6272 exhibited anti-proliferative activities superior to EPZ-6438 in some PCa models, wherein it induced p21 expression and cellular senescence by disrupting a methylation-independent PRC2 function. In summary, while EZH2i-based PROTACs failed to target the PRC2-independent functions of EZH2, they confer added benefits over EPZ-6438 by abolishing a polycomb-dependent but methylation-independent function of EZH2, offering therapeutic advantages in some PCa.

Histone lactylation, a recently discovered epigenetic modification, has been shown to play a critical role in regulating gene expression and cellular functions. However, its involvement in cisplatin (CDDP) resistance in non-small cell lung cancer (NSCLC) remains poorly understood. In this study, we demonstrated that histone lactylation is closely associated with CDDP resistance and correlates with poor prognosis of NSCLC. Mechanistically, H4K12la (histone e 4 lysine 12 lactylation) levels and CEBPB (CCAAT/enhancer-binding protein beta) had a cooperative effect on the regulation of AKR1C2 (Aldo-Keto reductase 1C2). Furthermore, AKR1C2 knockdown activates the mTOR oncogenic signaling pathway. Importantly, genetic manipulation of AKR1C2 or the combination of CDDP with an mTOR inhibitor effectively reverse CDDP resistance in NSCLC/CDDP cells. These findings highlighted the potential of AKR1C2 as a predictive biomarker for patient response to CDDP therapy. Additionally, our study established a novel link between histone lactylation and CDDP resistance, providing new insights into the epigenetic regulation in NSCLC.

While Stimulator-of-interferon genes (STING) is an innate immune adapter crucial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study results revealed that STING depletion promoted infiltration of CD4⁺ and CD8⁺ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.

Activating mutations in the ligand-binding domain of the estrogen receptor (ER)-encoding (ESR1) gene are present in up to 40% of metastatic breast cancer (BC) patients and are strongly associated with a high risk of liver metastasis (LM) formation. Using the MCF-7 BC model, we investigated whether the increased hepatic tropism of ESR1-mutated BC cells is driven by their metabolic adaptation to the liver microenvironment. Indeed, metabolomic analysis revealed elevated metabolites related to the urea cycle (UC) in LM-forming ESR1-mutated cells compared to wild-type (WT) ER-expressing cells, which failed to generate LM. The subsequent proteomic, western blotting, and qPCR analyses demonstrated a dramatic upregulation of the UC constituent, the mitochondrial ornithine/citrulline transporter SLC25A15, in liver-predilected ESR1-mutated cells relative to their WT counterpart cells. Unlike WT cells, ESR1-mutated cells readily formed spheroids and exhibited enhanced migration in liver mimicking hepatocyte-conditioned media. In addition, we employed a novel ex vivo approach where ESR1 mutated cells were seeded onto colonized fresh liver tissue-which was abolished by SLC25A15 knockout. Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.