Cell Death & Disease最新文献

Estrogen receptor-positive (ER+) breast cancer is the predominant subtype of breast cancer, and its development is closely linked to metabolic reprogramming, including alterations in cholesterol metabolism. Therefore, this study aimed to investigate the functional interplay between lysine demethylase 5B (KDM5B) and the Cullin-RING ligase 4B (CRL4B) complex in modulating cholesterol metabolism to promote ER+ breast cancer progression. Immunohistochemical assays and bioinformatic analysis of various cancer databases were performed to examine KDM5B expression levels in breast cancer. Additionally, KDM5B overexpression and knockdown were performed to investigate the role of KDM5B in breast cancer cell proliferation and progression. Notably, we identified physical and functional interactions between KDM5B and the CRL4B subunits, CUL4B and DDB1. Mechanistically, KDM5B recruits CRL4B to the promoters of INSIG1 and INSIG2, which are key regulators of cholesterol biosynthesis and uptake, and suppresses their expression by upregulating H2AK119ub1 and downregulating H3K4me3 histone marks, thereby promoting the proliferation, migration, and invasion of tumor cells. Functional assays revealed that disruption of the KDM5B-CRL4B axis impairs cholesterol homeostasis and inhibits tumor growth. KDM5B upregulation was significantly negatively correlated with the survival rates in various cancer types, including thyroid, lung, esophageal and colorectal cancers. Overall, these findings establish a novel regulatory axis in cholesterol metabolism, uncover potential therapeutic vulnerabilities in ER+ breast cancer, and suggest that targeting the KDM5B could provide a strategy to curb tumor progression.

The proneural-to-mesenchymal transition (PMT) is a pivotal process in glioblastoma (GBM), driving enhanced tumor aggressiveness, therapeutic resistance, and recurrence. HSPA5, a member of the heat shock protein 70 (HSP70) family, plays a crucial role in regulating and maintaining protein stability and function. Although HSPA5 is a recognized marker of poor prognosis in glioma, its underlying mechanistic function remains poorly defined. Here, we demonstrated that HSPA5 expression is highest in the mesenchymal (MES) subtype of GBM. The overexpression of HSPA5 in proneural (PN) cells induced PMT and promoted malignant phenotypes, whereas its knockdown in MES cells suppressed PMT and attenuated tumorigenicity. We further established that HSPA5 drives PMT by activating the YAP/TAZ pathway in vitro and in vivo. The expression of MES markers CD44 and c-MET was transcriptionally regulated by YAP/TAZ. Mechanistically, HSPA5 interacts directly with YAP/TAZ, disrupting their association with β-TrCP. This protective interaction inhibits the ubiquitination and proteasomal degradation of YAP/TAZ. Furthermore, HSPA5 expression was positively correlated with YAP and TAZ levels across GBM subtypes. Patients with high expression of HSPA5, YAP, and TAZ exhibited significantly poorer overall survival. Collectively, our findings suggested that HSPA5 promotes PMT through the stabilization of YAP/TAZ and identified HSPA5 as a promising therapeutic target for GBM patients.

Stress granules (SGs) are membrane-less organelles formed through liquid-liquid phase separation of proteins and RNAs, serving as temporary repositories for biomacromolecules to protect cells under stress conditions. Impaired SG disassembly is closely implicated in neurodegenerative diseases and aging, yet the mechanisms regulating SG dynamics are incompletely investigated. The constituents of heterogenous SGs are complicated and broadly categorized as core and shell components. In contrary to the relatively stable core components, our understanding of the diverse SG shell is deficient. By combining interactomic and proximity proteomic approaches, we reveal that the deubiquitinating enzyme OTUD6B is associated with SG-related functions. Immunofluorescence assays showed that OTUD6B localized to SGs, as well as regulated their early assembly and clearance, partially dependent on its enzymatic activity. Further proximity proteomics and interactomics results uncover the ATPase VCP/p97, a key SG disassembly factor, as an OTUD6B-associated protein. OTUD6B and VCP association is governed through their disordered regions normally participated in biomolecular condensation. VCP knockdown or pharmacological inhibition phenocopied OTUD6B silencing by leading to defects in SG dynamics. Mechanistically, SG coalescence of VCP incurred by OTUD6B in a partially enzymatic activity-dependent manner functions to accelerate not only the early assembly, but also SG clearance following stress removal. Therefore, our findings establish OTUD6B as a critical modulator of SG dynamics, linking its function to stress responses and potential disease mechanisms.

Pancreatic ductal adenocarcinoma (PDAC) cells undergo mitochondrial metabolic reprogramming to support their proliferation. However, the mechanisms by which mitochondrial protein quality control (MPQC) regulates cell metabolism remain unclear. Here, we found that c-Myc promotes PDAC cell proliferation by transcriptionally upregulating the expression of GRPEL1, an essential MPQC component. Mechanistically, c-Myc-regulated GRPEL1 maintains oxidative phosphorylation (OXPHOS) and minimizes ROS accumulation, thereby facilitating de novo fatty acid (FA) synthesis through the transcriptional upregulation of fatty acid synthase (FASN) expression. Targeting the c-Myc/GRPEL1 axis to block FASN-regulated FA synthesis inhibited PDAC cell proliferation and tumor growth in both cell models and patient-derived organoids (PDOs), whereas FA supplementation partially reversed this inhibitory effect. Clinically, c-Myc expression is positively associated with the levels of MPQC components in pancreatic ductal cells, with GRPEL1 ranking among the top hits. Furthermore, c-Myc, GRPEL1, and FASN are all expressed at higher levels in PDAC tissues than in peri-tumoral pancreatic tissues, and both c-Myc and GRPEL1 expression levels are positively correlated with that of FASN. These findings suggest that therapeutic inhibition of FA synthesis may be promising for treating PDAC patients with active c-Myc/GRPEL1/FASN signaling. Overall, this study demonstrates that FA synthesis mediated by the c-Myc/GRPEL1/FASN axis is essential for PDAC growth.

Cancer signaling encompasses a wide array of entangled molecular cascades that promote oncogenic progression and counteract the effect of tumor suppressors. Transforming growth factor β (TGFβ) induces complex and stage-dependent effects throughout tumor progression. During pre-malignant hyperplastic growth, TGFβ restricts cell proliferation and inflammation, while on the other hand, TGFβ promotes migration and distal metastasis of cancer cells. To dissect the temporal chromatin-based transcriptional response to TGFβ, we employed 3D culture models of isogenic human breast epithelial cells, exemplified by non-oncogenic MCF-10A (MI) and their HRAS-transformed counterpart (MII). Genome-wide chromatin accessibility profiling revealed an extensive chromatin opening induced by TGFβ at transcription start sites and enhancer elements in both models, with a marked enrichment of SOX4 binding motifs in oncogenic cells. Transcriptomic analyses unexpectedly revealed the upregulation of DNA replication and DNA damage response pathways, following TGFβ stimulation of oncogenic MII 3D cultures. Canonical TGFβ-driven programs, including epithelial-mesenchymal transition and metabolic reprogramming, were activated in both models. Notably, single-cell RNA-seq of primary breast tumors confirmed co-expression of SOX4 and cell cycle regulators. Mechanistically, we show that TGFβ induces the interaction between the MH2 domain of SMAD3 and the intrinsically disordered regions of SOX4, co-activating downstream gene targets. Validating the genome-wide analyses, we found that resistance of breast cancer cells to the CDK4/6 inhibitor palbociclib conferred by TGFβ stimulation was functionally dependent on SOX4. Collectively, our findings reveal an apparent oncogenic function of TGFβ in promoting cell cycle progression and drug resistance through SOX4, highlighting the pro-tumorigenic role of TGFβ signaling in breast cancer progression.

Immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have been targeted in cancer therapy, however, the efficacy of these interventions remains limited. Beyond its immune function on T cell surfaces, CTLA-4 is also expressed in various intrinsic cancer cells, where it influences cell proliferation, metastasis, and apoptosis. The present study aimed to investigate the function of CTLA-4 in cancer cells by investigating the consequences of CTLA-4 depletion in melanoma cells. We found that targeting CTLA-4 in melanoma cells inhibited proliferation via the induction of senescence, which was attributed to genomic instability resulting from a decrease in Aurora B expression, leading to the activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-stimulator of interferon genes (STING) pathway. Notably, DNA-PKcs coordinates CTLA-4 depletion-induced senescence by regulating the STING pathway. Mouse study showed that the tumor suppressive effect of CTLA-4 depletion in allograft cancer models via senescence induction. Furthermore, public data analysis showed a negative correlation between CTLA-4 and DNA-PKcs expressions in patients. Conclusively, CTLA-4-depletion induces senescence via genome instability, which activates DNA-PKcs and ultimately leads to cancer growth regression. These findings suggest that intracellular CTLA-4 targeting can confer to cancer therapy.CTLA-4 depletion-induced senescence in cancer. CTLA-4 depletion-induced senescence in cancer. CTLA-4 deficiency induces senescence via the DNA PKcs-STING-AKT pathway in cancer cells. When CTLA-4 is depleted in cancer cells, the genome becomes unstable due to the reduction of Aurora B expression, then consequently DNA damage occurs accompanied by micronuclei formation in the cytosol. Subsequently, DNA-PKcs is activated and sequentially promotes the STING-AKT-p21 signaling pathway, which mediates cellular senescence and eventually prevents tumor growth.