Oncogene最新文献

Pituitary adenomas (PAs) are intracranial tumours with severe clinical complications and increased morbidity. Stem cell-like characteristics play a crucial role in the initiation and progression of PAs. In this study, we identified CDK8 as a critical regulator of stemness in PA tumorigenesis. Immunohistochemical analysis demonstrated that CDK8 expression is elevated in clinical PA samples and correlates significantly with Knosp grades, indicating its potential role in parasellar invasion. Inhibition of CDK8 significantly impaired the self-renewal capacity of patient-derived PA stem-like cells (PASCs), as evidenced by reduced tumoursphere formation. To elucidate the underlying mechanism, we found that CDK8 phosphorylates the pluripotency transcription factor SOX2, thereby disrupting its interaction with the E3 ubiquitin ligase HERC5 and preventing SOX2 degradation through the ubiquitin-proteasome pathway. Moreover, pharmacological inhibition of CDK8 markedly suppressed PA cell proliferation and viability in GH3 and MMQ cell lines, primary human PA cells, and murine xenograft models. These findings revealed a novel regulatory mechanism of PA stemness and provided a promising therapeutic target for PA.

Gastric cancer remains a significant global health challenge. Lymph node metastasis (LNM) has been identified to be relevant to the prognosis of gastric cancer (GC). However, its mechanisms of progression and metastasis are still not fully understood. Recently, S100A10 has been verified to be aberrantly expressed in various cancers. In this study, we found that S100A10 expression was significantly upregulated in metastatic GC tissues. S100A10 remarkably accelerated tumor metastasis and growth. Mechanistically, dual-luciferase assay and chromatin immunoprecipitation revealed that c-Jun could bind to the promoter region of S100A10 and activate its transcription. Meanwhile, S100A10 competitively bound to Vimentin, preventing it from interacting with ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52), which led to a reduction in K48-linked ubiquitination of vimentin and an increase in vimentin protein levels in GC cells. Subcutaneous xenograft and lung metastasis mouse models were established to prove that targeting inhibition of S100A10 could effectively suppressed tumor metastasis and growth in vivo. In conclusion, S100A10, activated by c-Jun, remarkedly promoted metastasis and proliferation in GC via suppressing vimentin-UBA52 interaction.

The MYC transcription factor is a key regulator of growth during development and a potent cancer driver when its expression is dysregulated. Strategies to inhibit MYC oncogenic activity would mark a significant advance, but decades of efforts to target MYC directly have not been fruitful. Understanding how MYC drives transformation and tumor growth may provide new therapeutic avenues in a variety of cancers. By intersecting two independent genome-wide screens, we identified loss of the chromatin remodeler Chromodomain-Helicase DNA-binding 1 (CHD1) as a potential synthetic lethal target in MYC-driven breast cancer. Knockdown of CHD1 in a xenograft model of MYC-driven breast cancer suppresses tumor growth in vivo. In tissue culture models, we found that knockdown of CHD1 suppresses cell proliferation and induces cell death, specifically when MYC is overexpressed. Mechanistically, we found that CHD1 is required to maintain an open chromatin landscape and a transcriptional program associated with cancer progression in MYC overexpressing breast cells. Follow-up experiments indicate that this synthetic lethality may arise from nucleolar stress and p53 activation. These findings provide new insights on the chromatin-level regulation of MYC-driven breast cancer and uncover CHD1 as a novel synthetic vulnerability and potential therapeutic target.

Glucocorticoids are frequently administered to alleviate therapy-related side effects in cancer patients, yet their role in tumor progression remains controversial and mechanistically unresolved. Here, we demonstrate that the long-acting glucocorticoid dexamethasone (Dex) exerts antitumor effects that are mediated by neutrophils. In murine models of Lewis lung carcinoma (LLC) and B16F10 melanoma, Dex markedly suppressed tumor growth and prolonged survival of tumor-bearing mice. These effects were independent of adaptive immunity, macrophages, and tumor cell-intrinsic glucocorticoid signaling, but required functional glucocorticoid receptor (GR) signaling in neutrophils. Dex-treated neutrophils exhibited longer survival and higher cytotoxicity toward tumor cells via increased production of reactive oxygen species (ROS). Disruption of this GR-ROS axis, either through neutrophil-specific GR deletion or pharmacological inhibition of ROS, abolished the antitumor activity of Dex. Together, these findings uncover a neutrophil-mediated tumoricidal function of Dex and suggest that neutrophil GR-ROS signaling may be harnessed for cancer therapy.

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 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).

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.

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.

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 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^ENZR, CWR-R1^ENZR, and VCaP^ENZR) 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^ENZR cells, suggesting an AR-dependent mechanism of ENZ resistance. AHR promotes neuroendocrine differentiation while suppressing the expression of AR/GR targets in C4-2B^ENZR 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.