Cell Death & Disease最新文献

Clear cell renal cell carcinoma (ccRCC) is characterized by disrupted lipid metabolism, traditionally attributed to VHL mutations and HIF stabilization. Here, we identified CEBPB as an epigenetically upregulated, VHL-independent transcription factor driving ccRCC tumorigenesis. CEBPB was regulated by H3K27ac and H3K4me and transcriptionally repressed the tumor-suppressive glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), thereby elevating dihydroxyacetone phosphate (DHAP)-derived ether lipid synthesis and enhancing Akt signaling. This activation suppressed CPT1A expression, inhibiting fatty acid oxidation (FAO) and leading to lipid accumulation, as found by lipidomics and isotope tracing. Loss of CEBPB reduced ether lipids, reactivated CPT1A, and impaired Akt signaling, diminishing tumor growth and lipid content in vitro and in vivo. Restoration of ether lipids or Akt activity rescued these effects. Importantly, CEBPB expression and enhancer activation were not modulated by VHL status and it could be targeted pharmacologically. The CEBPB-GPD1L-ether lipid-Akt-CPT1A axis is proposed as a new druggable driver in ccRCC integrating epigenetics, transcription, intermediary metabolism and oncogenic signaling.

Lactate, a key byproduct of glycolysis in tumor cells, has emerged as more than just a metabolic waste product. Increasing evidence reveals that lactate and its associated post-translational modification (PTM), lactylation, play multifaceted roles in regulating various forms of regulated cell death (RCD), thereby contributing to cancer proliferation, therapy resistance, and immune exclusion. Notably, evasion of RCD is a hallmark of cancer and targeting RCD may represent a promising therapeutic strategy for cancer treatment. In this review, we focus on summarizing the dual and context-dependent roles of both lactate and lactylation in modulating distinct types of RCD, including apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis. Moreover, we further discuss how RCD processes impact lactate metabolism and highlight the therapeutic potential and current challenges of targeting the lactate-lactylation-RCD axis in cancer treatment.

The hyper-activation of the Hippo/YAP axis was observed in triple-negative breast cancer (TNBC), which was crucial for tumor progression. The over-activation of YAP in TNBC remains unexplained, despite the continued functionality of the inhibitory phospho-cascade. Recently, studies revealed that the ubiquitin modifications of YAP also play important roles in the Hippo/YAP axis and cancer progression. In order to understand the potential mechanisms of ubiquitination and deubiquitination process in YAP function, we carried out siRNA screening for critical deubiquitinases in TNBC. Via the deubiquitinases (DUB) library, we identified Ubiquitin Specific Peptidase 8 (USP8) as an important effector in YAP function and TNBC progression. Inhibition of USP8 hampered TNBC progression via Hippo signaling. Clinical data revealed that USP8 expression correlated with YAP protein level and poor survival in TNBC patients. Biochemical evaluations revealed that USP8 has the ability to connect with YAP and suppress K48-linked polyubiquitination, thereby enhancing the stability of YAP. Interestingly, YAP directly binds to the USP8 promoter region, enhancing its transcription in TNBC. Our study revealed a forward feedback loop between USP8 and Hippo signaling in TNBC, indicating USP8 as a potential therapeutic drug targets in TNBC.

PTPN18 is a member of the PEST (proline-glutamic acid-serine-threonine rich sequence) protein tyrosine phosphatase subfamily that has been intensively studied in immune cells. Here, we identified a novel PTPN18-interacting protein, fibrillarin (FBL), through mass spectrometry analysis and clarified the binding sites and interaction motifs via peptide mapping. The R451 site of PTPN18 and the V187 site of FBL dominate the interaction between PTPN18 and FBL. Further studies suggest that PTPN18, but not PTPN18 R451A, can dephosphorylate the Y313 site of FBL and can reduce the protein expression level of FBL by promoting its ubiquitin proteasome degradation. In addition, PTPN18 can affect its downstream functions, including the MAPK signaling pathway and methylation of rRNA 2'-O and histone H2AQ104 sites, as well as RNA synthesis through negative regulation of FBL, whereas PTPN18 R451A cannot. As a result, the interaction between PTPN18 and FBL affects the proliferation and apoptosis of breast cancer cells, thus inhibiting tumor growth. This study reveals a novel mechanism through which PTPN18 inhibits breast cancer progression and further refines the PTPN18 protein interaction network, which is important for understanding its role in cell signaling, revealing disease mechanisms, discovering new drug targets, and developing new treatments.

Despite the high prevalence of metabolic dysfunction-associated steatohepatitis (MASH), the number of effective therapeutic targets is limited due to a vague understanding of its intricate pathogenesis. In this study, we reported that the expression of nuclear factor erythroid-derived 2-related factor 1 (NRF1), an endoplasmic reticulum (ER) membrane-bound transcription factor that governs the expression of proteasome subunit genes, was significantly reduced in liver tissues from MAFLD patients and from mice fed a high-fat diet (HFD) for 20 weeks. Liver-specific overexpression of NRF1 in mice markedly ameliorated HFD-driven hepatic steatosis, liver injury and inflammation. Elevated NRF1 expression restored the function of the proteasome, facilitating the degradation of unfolded and nonfunctioning proteins, thereby mitigating ER stress and reducing oxidative stress. Moreover, docosahexaenoic acid (DHA) was found to increase NRF1 expression, contributing to the amelioration of MASH. Mechanistically, DHA inhibited the ubiquitination of NRF1 via the cytoplasmic E3 ligases FBW7 and HRD1 at the ER membrane, thereby preventing its degradation. Liver-specific knockdown of NRF1 abrogated the protective effect of DHA on HFD-driven MASH in mice. Together, our findings underscore the pivotal role of NRF1 in the DHA-mediated amelioration of MASH and suggest that NRF1 is a potential therapeutic target for MASH management.

Interferon-beta (IFN-β) has potent antitumor activity, but its clinical therapeutic potential is undermined by intrinsic negative feedback loops that suppress IFN-β production. However, the feedback mechanisms regulating IFN-β homeostasis in non-small cell lung cancer (NSCLC) remain unclear. We found that tripartite motif containing 3 (TRIM3) promotes the transcription and mRNA expression of IFNB1. Conversely, excessive IFN-β inhibits expression of TRIM3, creating their reciprocal feedback loop. Mass spectrometry revealed that toll-like receptor 3 (TLR3), a key sensor that triggers IFN-β production, is the interacting partner of TRIM3. Following the elucidation of the interactive mode between TRIM3 and TLR3, we found that activation of the TRIM3/TLR3 axis induced IFN-β secretion and overrode the feedback inhibition. Sustained IFN-β secretion subsequently inhibits NSCLC cell proliferation and reprograms the tumor microenvironment by increasing the infiltration levels of CD4⁺ T cells, M1 macrophages and NK cells. Our findings revealed a reciprocal negative feedback loop in the regulation of IFN-β signaling, highlighting the role of the TRIM3/TLR3 axis in the suppression of NSCLC progression and offering a promising strategy to suppress tumor growth and enhance immunotherapy efficacy in NSCLC.

Multiple myeloma (MM) cells originate from antibody-producing plasma cells and endure chronic oxidative and proteotoxic stress due to the excessive production of immunoglobulins and free light chains. We previously demonstrated that CD56 (also known as neuronal cell adhesion molecule 1) promotes cAMP-responsive element binding (CREB1) activation in MM cells to drive survival, without fully elucidating its mechanism of action. In this study, we describe the global role of CREB1 in regulating tolerance to cellular stresses in MM. Here, we present data to demonstrate that CREB1 directly or indirectly influences key proteins involved in the clearance of oxidants, the unfolded protein response (UPR), and autophagy. In silico data from real patients with MM showed that patients with high CREB1 expression have greater activation of gene sets associated with endurance of stress. We confirmed by genomic and pharmacological modulation that CREB1 activates the mTOR pathway, halting autophagy, and directly binds to the promoter of NRF2 and PERK, modulating genes involved in oxidation and protein stress adaptation. Of particular importance was the identification of TXNIP among the regulated genes. Notably, the TXNIP gene belongs to the 1q21 cytoband, which is amplified in 30 percent of patients with MM, leading to poor outcomes. We showed for the first time that TXNIP inhibition is also toxic against MM cells, interfering with UPR and autophagy. Thus, our data highlights the essential roles of CREB1 and TXNIP in MM cell survival under chronic stress, providing new insights into MM pathophysiology and novel therapeutic strategies for patients with high-risk disease.

Elucidation of the molecular mechanism underlying metastatic dissemination in patients with high-grade serous ovarian carcinoma (HG-SOC) has the potential to affect patient outcome. This study explores the role of gasdermins (GSDMs) in HG-SOC, focusing on novel pyroptosis-independent nuclear functions of GSDME, which are integrated with the endothelin-1 (ET-1)/ET-1 receptor A (ET_AR) signaling to sustain metastatic progression. In this tumor, GSDME upregulation is correlated to epithelial-mesenchymal transition (EMT) and ET_AR expression. ET-1 signaling fuels GSDME expression by inducing its transcription via the core EMT factors, ZEB1 and ZEB2. GSDME, in turn, translocates to the nucleus to engage ZEB1 and transcriptionally regulate genes coupled with EMT and inflammatory signals, such as E-cadherin, vimentin and interleukin (IL)-6. GSDME depletion, similarly to ZEB1 and ET_AR blockade, restrains ET-1-induced EMT phenotypic plasticity and inflammatory cytokine release. Clinically relevant, ET-1 receptor (ET-1R) antagonist, by depleting the nuclear reservoir of the GSDME/ZEB1 transcriptional complex, hinders the metastatic traits of HG-SOC. The intertwined ET_AR/GSDME/ZEB1 circuitry characterizes mesenchymal HG-SOC patients and associates with a high-risk of poor survival. Together, these findings unveil GSDME as a key transcriptional regulator of aggressive behaviors and worse prognosis in HG-SOC patients, in an ET-1-driven alliance with ZEB1, which could be targeted by ET-1R antagonist to reduce the metastatic burden of this tumor.

Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, accounting for 7-10% of all children cancers, but leading to 15% of childhood cancer related deaths. Children with high-risk neuroblastoma (HR-NBL) lack effective treatments that achieve durable outcomes. While multiple factors stratify NBL patients into the high- risk category, MYCN amplification is a crucial determinant for that group. Thus far, efforts towards directly targeting MYCN have proven unsuccessful. Serine/threonine protein phosphatase 2 A (PP2A) functions as a tumor suppressor across cancers through its epigenetic effects, and its activity and tumor suppressor function are inhibited in NBL. We hypothesized that MYCN may be a target for PP2A, and that reactivation of PP2A may have a tumor suppressive effect on NBL. We employed studies to document the phenotypic, epigenetic, and in vivo effects of pharmacologic PP2A activation. Novel PP2A activators, ATUX-1215 or ATUX-5800, reduced MYCN mRNA abundance and MYCN phosphorylation and protein expression. PP2A activation decreased the acetylation of H3K27 (H3K27ac) as well as the enrichment of H3K27ac at the MYCN promoter. ATUX-1215 and ATUX-5800 treatment led to hypophosphorylation of RNA Pol II carboxy-terminal domain (CTD) and BRD4, transcriptional and epigenetic regulators respectively, coinciding with decreased MYCN expression and gene regulator acetylation. Tumor growth decreased in animals treated with ATUX-1215, and analysis of tumor specimens confirmed decreased MYCN expression. We conclude that pharmacologic PP2A reactivation may be a relevant therapeutic component in NBL treatment through its targeting of MYCN.