Cell Death & Disease最新文献

Pancreatic ductal adenocarcinoma (PDAC) radiotherapy (RT) resistance is frequently mediated by an immunosuppressive tumor microenvironment (TIME). Utilizing an in vivo CRISPR-Cas9 metabolic enzyme screen, we identified fucosyltransferase 2 (FUT2) as a potent non-catalytic enhancer of RT response. Mechanistically, FUT2 scaffolds the E3 ubiquitin ligase FBXO2, facilitating K362 site-specific ubiquitination and proteasomal degradation of the transcription factor NR2F2. This degradation suppresses expression of the immunosuppressive factor Lipocalin-2 (LCN2), which drives CD8⁺ T cell exhaustion and impedes NK cell infiltration, fostering a radioresistant TIME. Interestingly, we observed that RT could reduce FUT2 transcript levels via an METTL14-mediated m⁶A RNA methylation, while NR2F2 was identified to transcriptionally upregulate METTL14, establishing a feedforward inhibitory loop that sustains FUT2 suppression. Clinically, FUT2 expression positively correlates with CD8⁺ T cell infiltration and prolonged survival in RT-treated PDAC patients. Preclinically, combining RT with LCN2-neutralizing antibodies elicited synergistic anti-tumor immunity. These results unveil FUT2 as a regulator of PDAC radiosensitivity via the FUT2-FBXO2-NR2F2-LCN2 axis, offering a promising therapeutic target to overcome RT resistance.

The topoisomerase I inhibitor topotecan is an effective chemotherapeutic agent for retinoblastoma; however, treatment resistance remains a major clinical challenge, and its mechanisms remain elusive. Using genome-wide CRISPR-Cas9 knockout screening, we identified ELF2 as a key gene involved in topotecan resistance. Here, we show that surviving retinoblastoma cells exposed to topotecan showed progressively decreased ELF2 expression, accompanied by reduced apoptosis. In a mouse xenograft model, ELF2 disruption diminished the antitumor efficacy of topotecan, with ELF2-knockout cells exhibiting reduced topotecan-induced apoptosis. RNA sequencing further revealed that the MT-CYB pathway, associated with ATP synthesis, contributes to ELF2-mediated resistance. Importantly, clinical analysis demonstrated a correlation between ELF2 expression and tumor volume in retinoblastoma patients treated with topotecan. Together, these findings interrogate the mechanisms underlying topotecan resistance in retinoblastoma and suggest ELF2 as a potential therapeutic target to overcome drug resistance.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor with high metastasis rates and poor prognosis. This study investigated the role of NOP2/Sun RNA methyltransferase family member 2 (NSUN2), a key 5-methylcytosine (m5C) methyltransferase, and m5C methylation in the progression of OSCC, particularly in relation to ferroptosis resistance. NSUN2 is significantly overexpressed in OSCC tissues and cell lines and its high expression correlates with poor prognosis and aggressive tumor characteristics. Knockdown of NSUN2 in ferroptosis-resistant OSCC cells resulted in increased sensitivity to ferroptosis. Conversely, NSUN2 overexpression conferred ferroptosis resistance, reducing iron accumulation and restoring GPX4 expression even under erastin treatment. Mechanistically, NSUN2 mediates m⁵C modification of sequestosome 1 (SQSTM1)/P62 mRNA, and the m5C reader protein Y-box binding protein 1 (YBX1) enhances SQSTM1/P62 mRNA stability. This regulation suppresses autophagy and thereby inhibits autophagy-dependent ferroptosis in OSCC. In vivo xenograft models confirmed that NSUN2 knockdown significantly inhibited tumorigenicity. Notably, treatment with an autophagy inhibitor (3-MA) or a ferroptosis inhibitor (Fer-1) partially restored tumor growth in NSUN2-knockdown cells, validating the critical role of autophagy and ferroptosis in NSUN2-mediated OSCC progression. These findings identify the NSUN2-YBX1-SQSTM1/P62 axis as a key regulator of autophagy-dependent ferroptosis in OSCC, highlighting NSUN2 as a promising epitranscriptomic target to enhance ferroptosis induction for OSCC therapy.

The early detection and precise treatment of gastric cancer (GC) remain critical challenges worldwide. In this work, we screened and identified a subset of highly aggressive GC cell lines that exhibit elevated expression of TRIM24 using transwell assays and animal models. TRIM24 showed enhanced expression in GC cells and gastric carcinoma tissue samples in comparison with gastric noncancerous tissues. Importantly, elevated TRIM24 levels correlated with advanced tumor stage and poorer clinical outcomes. Functionally, TRIM24 acted as an oncogene, driving GC proliferation, invasion, and metastasis both in cell culture and animal experiments. Notably, TRIM24 knockdown markedly inducted apoptosis in GC cells through the modulation of NRBP1, a known context-specific tumor suppressor. Mechanistically, TRIM24 bound to NRBP1, enhancing its ubiquitination and subsequent degradation. Further mechanistic insights revealed that NRBP1 phosphorylation at residue S42 was crucial for TRIM24-mediated ubiquitination, with residue K430 identified as the specific ubiquitination site targeted by TRIM24. Jointly, the above findings unveil a critical role for TRIM24 in GC tumorigenesis and metastatic progression, thereby positioning TRIM24 as a promising therapeutic target in GC management.

Programmed cell death is crucial for organ morphogenesis and tissue homeostasis. Understanding programmed cell death in the developing brain is essential for comprehending both normal brain development and neurological disorders. In this study, we utilize Cajal-Retzius (CR) cells, transient neurons that populate the embryonic cortex and are predominantly eliminated in early postnatal stages, as a model to investigate the regulation of programmed cell death. While many CR cells typically undergo postnatal cell death, some persist into adulthood in the hippocampus, influencing local circuits and behaviors. Here, we show that the loss of capicua (CIC), a transcriptional repressor implicated in a rare neurodevelopmental syndrome and multiple cancers, results in aberrant survival of CR cells in the adult hippocampus. Altered cell survival is mediated by the cell-autonomous function of CIC in hippocampal CR cells. Surprisingly, the atypical persistence of CR cells following CIC loss does not impact hippocampal-dependent behaviors or susceptibility to kainic acid-induced seizures. Single-cell transcriptomic analysis unveils previously unrecognized heterogeneity among hippocampal CR cells and suggests a role of CIC in repressing Fgf1 expression. Additionally, we reveal that FGF1 and BCL2 serve as pivotal regulators enhancing CR cell survival in the postnatal hippocampus. Our findings shed light on a previously unacknowledged role of CIC upstream of FGF signaling and elucidate the apoptosis mechanism governing developmental programmed CR cell death.

Metastatic melanoma (MM) displays remarkable phenotypic plasticity, allowing tumor cells to transition reversibly between proliferative and mesenchymal (MES)-like states. This dynamic switching is strongly associated with therapeutic resistance and poor prognosis. Although transcriptional and epigenetic mechanisms driving these transitions have been extensively studied, the role of post-translational regulation, particularly the ubiquitin-proteasome system, remains poorly understood. Here, we identify the ubiquitin E3 ligase RNF 123 (KPC1) as a key post-translational suppressor of MES reprogramming in MM. Integrative analyses of bulk and single-cell transcriptomic datasets revealed that KPC1 expression is inversely correlated with the expression of core mesenchymal markers such as ZEB1, CDH2, and AXL, and positively associated with epithelial and melanocytic lineage genes, including CDH1 and MITF. Deconvolution of TCGA-SKCM RNA-seq data confirmed that this inverse correlation is specific to malignant melanoma cells and strongest in tumors enriched for mesenchymal gene signatures. Single-cell trajectory and enrichment analyses further demonstrated that decreasing KPC1 expression accompanies MES-like switch. Mechanistically, KPC1 binds and promotes the ubiquitination and proteasomal-mediated degradation of ZEB1, thereby suppressing cadherin switching and cell motility. Loss of KPC1 in melanoma cells prevented ZEB1 proteasomal-mediated degradation, increased expression of mesenchymal markers, and enhanced MM cells migration. Clinically, low KPC1 protein levels were associated with increased expression of ZEB1 and CDH2 and poorer overall survival. Furthermore, combined assessment of KPC1, ZEB1, and CDH2 expression improved patient stratification, suggesting the potential utility of multi-marker signatures for prognostic modeling. These findings establish KPC1 as a central post-translational regulator of melanoma cell state plasticity through targeted degradation of ZEB1. This study highlights a novel mechanism regulating MES-like transition and highlights KPC1 as a potential theragnostic target in MM.