Oncogene最新文献

Triple-negative breast cancer (TNBC) is an aggressive and heterogenous breast cancer subtype. RASAL2 is a RAS GTPase-activating protein (GAP) that has been associated with platinum resistance in TNBC, but the underlying mechanism is unknown. Here, we show that RASAL2 is enriched following neoadjuvant chemotherapy in TNBC patients. This enrichment is specific to the tumour compartment compared to adjacent normal tissues, suggesting that RASAL2 upregulation is tumour-selective. Analyses based on 2D/3D cultures and patient-derived xenograft models reveal that RASAL2 confers cross-resistance to common DNA-damaging chemotherapies other than platinum. Mechanistically, we found that apoptotic signalling is significantly downregulated upon RASAL2 expression. This feature is characterised by substantial alterations in the expression of anti-versus pro-apoptotic factors, pointing to heterogeneous mechanisms. In particular, RASAL2 upregulates BCL2 via activation of the oncogenic transcription co-factor YAP. CREB1, a YAP-interacting protein, was identified as the common transcription factor that binds to the promoter regions of RASAL2 and BCL2, driving their collective expression. A subset of RASAL2 colocalises with BCL2 subcellularly. Both proteins decorate mitochondria, where the high levels of mitochondrial RASAL2-induced BCL2 expression render the organelles refractory to apoptosis. Accordingly, mitochondrial outer membrane permeabilisation assay using live mitochondria from RASAL2-high/chemoresistant tumour cells demonstrated attenuated release of death signal, cytochrome c, when exposed to pro-apoptotic factors BAX and tBID. Similarly, these cells were more resilient towards chemotherapy-induced mitochondrial depolarisation. Together, this work reveals a previously undocumented molecular link between RAS GAP and apoptosis regulation, providing a new mechanistic framework for targeting a subset of chemorefractory tumours.

Overexpression of uridine-cytidine kinase 2 (UCK2), a key enzyme in the pyrimidine salvage pathway, is implicated in human cancer development, while its regulation under nutrient stress remains to be investigated. Here, we show that under glucose limitation, AMPK phosphorylates glycinamide ribonucleotide formyltransferase (GART) at Ser440, and this modification facilitates its interaction with UCK2. Through its binding to UCK2, GART generates tetrahydrofolate (THF) and thus inhibits the activity of integrin-linked kinase associated phosphatase (ILKAP) for removing AKT1-mediated UCK2-Ser254 phosphorylation under glucose limitation, in which dephosphorylation of UCK2-Ser254 tends to cause Trim21-mediated UCK2 polyubiquitination and degradation. In this way, both UCK2 binding ability and THF producing catalytic activity of GART protect protein stability of UCK2 and pyrimidine salvage synthesis, and sustain tumor cell growth under glucose limitation. In addition, UCK2-Ser254 phosphorylation level displays a positive relationship with GART-Ser440 phosphorylation level and its enhancement is correlated with poor prognosis of human hepatocellular carcinoma (HCC) patients. These findings reveal a non-canonical role of GART in regulating pyrimidine salvage synthesis under nutrient stress, and raise the potential for alternative treatments in targeting pyrimidine salvage-dependent tumor growth.

Ferroptosis is a unique modality of regulated cell death induced by excessive lipid peroxidation, playing a crucial role in tumor suppression and providing potential therapeutic strategy for cancer treatment. Here, we find that aldehyde dehydrogenase-ALDH3A1 tightly links to ferroptosis in squamous cell carcinomas (SCCs). Functional assays demonstrate the enzymatic activity-dependent regulation of ALDH3A1 in protecting SCC cells against ferroptosis through catalyzing aldehydes and mitigating lipid peroxidation. Furthermore, a specific covalent inhibitor of ALDH3A1-EN40 significantly enhances the ferroptosis sensitivity induced by the ferroptosis inducer. The combination of EN40 and a ferroptosis inducer exhibits a synergistic effect, effectively inhibiting the proliferation of SCC cells/organoids and suppressing tumor growth both in vitro and in vivo. On mechanism, high expression of ALDH3A1 is transcriptionally governed by TP63, which binds to super-enhancer of ALDH3A1. Collectively, our findings reveal a yet-unrecognized function of ALDH3A1 exploited by SCC cells to evade ferroptosis, and targeting ALDH3A1 may enhance the effect of ferroptosis-induced therapy in SCCs.

Smoking plays an underappreciated role in breast cancer progression, increasing recurrence and mortality in patients. Here, we show that S100A8/A9 innate immune signaling is a molecular mechanism that identifies smoking-related breast cancers and underlies their enhanced malignancy. In contrast to acute exposure, chronic nicotine increased tumorigenicity and reprogrammed breast cancer cells to express innate immune response genes. This required the α7 nicotinic acetylcholine receptor, which elicited dynamic changes in cell differentiation, proliferation, and expression of secreted cytokines, such as S100A8 and S100A9, as assessed by unbiased scRNA-seq. Indeed, pharmacologic or genetic inhibition of S100A8/A9-RAGE receptor signaling blocked nicotine's tumor-promoting effects. We also discovered Syntaphilin (SNPH) as an S100A8/A9-dependent gene enriched specifically in estrogen receptor-negative (ER^-) cancers from former smokers, linking this response to patient disease. Together, our findings describe a new α7 nAChR-S100A8/A9-Syntaphilin immune signaling module that drives nicotine-induced tumor progression and distinguishes smoking-related patient disease as a distinct subset of aggressive breast cancers.