Jianxiu Yu

Multiple myeloma (MM) is a refractory plasma cell neoplasm characterized by frequent development of drug resistance, leading to poor clinical outcomes. Activation of ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a promising cancer therapeutic strategy. In this study, we show that the circular RNA circ_0042819 exhibits high expression in both bone marrow and plasma samples from MM patients, with its overexpression strongly associated with disease progression and unfavorable prognosis. Mechanistically, circ_0042819 directly interacts with Up-frameshift protein 1 (UPF1) in MM cells, and the circ_0042819-UPF1 complex upregulates the expression of phospholipase A2 group VI (PLA2G6) via interacting with, and thus stabilizing, its mRNA. Furthermore, the circ_0042819-PLA2G6 axis suppresses ferroptosis through phospholipid remodeling in MM cells. Importantly, depletion of circ_0042819 or PLA2G6 enhances MM sensitivity to proteasome inhibitors (bortezomib and carfilzomib) by promoting ferroptosis both in vitro and in vivo. Collectively, our findings demonstrate that circ_0042819 is a potential non-invasive biomarker for the diagnosis and prognosis of MM, and that inhibition of the circ_0042819-PLA2G6 axis can mitigate the resistance of MM to proteasome inhibitors through ferroptosis sensitization, thus suggesting a novel therapeutic approach.

Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies despite frequent hyperactivation of the PI3K/AKT pathway, and the contribution of adaptor proteins to this process remains poorly defined. Here, we identify Insulin Receptor Substrate 4 (IRS4) as a common substrate of Src kinase and the phosphatase RPTPα, and uncover a previously unrecognized, conserved phosphorylation site at YY111/112 within the IRS4 PH domain. Src-mediated phosphorylation at this site is essential for IRS4-driven proliferation, anchorage-independent growth, and invasiveness in LUSC cells. Mechanistically, phosphorylation at YY111/112 induces conformational rearrangements in IRS4 that enhance the recruitment of the p85β SH2 domain to the YXXM motif of IRS4, thereby promoting AKT activation without altering IRS4 protein stability or subcellular distribution. An IRS4-derived cell-permeable phosphopeptide containing pYY111/112 disrupts the Src–IRS4 interaction and significantly suppresses tumor growth in vivo in a YY111/112-dependent manner. Consistently, YY111/112 phosphorylation is markedly elevated in human LUSC tissues and correlates with advanced disease stages. Collectively, these findings define a Src–IRS4–PI3K/AKT signaling axis and identify YY111/112 as a critical regulatory site of IRS4 and a potential therapeutic vulnerability in LUSC

Despite significant advances in the treatment of non-small cell lung cancer (NSCLC), acquired resistance remains a major obstacle in advanced stages. Elucidating the molecular mechanisms underlying resistance is crucial for improving clinical outcomes, overcoming therapeutic limitations, and developing effective combination strategies. Here, we identify TRIM25 as a key driver of tumor progression and chemoresistance by promoting the destabilization of AGO2. Mechanistically, TRIM25 directly binds to AGO2 and induces its polyubiquitination, triggering proteasomal degradation. This process downregulates miR-148b-5p, a tumor-suppressive miRNA that post-transcriptionally represses ABCC1 to counteract chemoresistance. Knockdown of TRIM25 restores AGO2 stability by attenuating ubiquitination, thereby reinstating miR-148b-5p-mediated suppression of ABCC1. Functionally, the TRIM25–AGO2–miR-148b-5p–ABCC1 axis inhibits tumor growth and re-sensitizes NSCLC cells to chemotherapy. Notably, therapeutic delivery of miR-148b-5p mimics robustly suppresses NSCLC progression and overcomes chemoresistance in cell lines, xenografts, and patient-derived xenograft (PDX) models, highlighting its translational potential. Our study unveils a previously unrecognized regulatory axis governing chemoresistance in NSCLC, providing both mechanistic insights and novel therapeutic avenues to combat treatment resistance.

Stress granules (SGs) are cytoplasmic, membraneless organelles that modulate mRNA metabolism and cellular adaptation under stress, yet the mechanisms by which they regulate cancer cell survival remain unclear. Here, we identify Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1), a core SG component, as stress-inducible SUMOylation target. Upon various stress conditions, SUMOylated PABPC1 promotes SG assembly and enhances cancer cell survival. Transcriptome-wide analysis reveals that SUMOylated PABPC1 selectively stabilizes mRNAs enriched in conserved U-rich elements. Mechanistically, SUMOylated PABPC1 interacts with RNA-binding protein TIA1 to form PABPC1–SUMO–TIA1 complex that recruits U-rich mRNAs into SGs, protecting them from degradation. This process facilitates the expression of U-rich genes, such as mitophagy-related genes FUNDC1, BNIP3L, thereby maintaining cellular homeostasis and promoting cell survival under adverse conditions. Our findings reveal that PABPC1 SUMOylation connects stress granule assembly with selective U-rich mRNA stabilization and mitophagy, promoting cancer cell stress adaptation.

Metabolic reprogramming is a hallmark of cancer, with dysregulated lipid metabolism contributing to tumor progression and therapy resistance. This study identifies the DNA demethylase TET3 as a key regulator of lipogenic metabolism in pancreatic ductal adenocarcinoma (PDAC). TET3 expression is elevated in the lipogenic PDAC subtype and correlates with poor patient prognosis. Genetic ablation of TET3 disrupts lipid homeostasis, alters the saturated‐to‐monounsaturated fatty acid ratio, and reduces proliferative capacity. Mechanistically, TET3 represses GATA6 expression through recruitment of histone deacetylases (HDACs) to its promoter, leading to H3K27 deacetylation, independent of its catalytic activity. Loss of TET3 derepresses GATA6 , which in turn suppresses lipogenic enzymes, such as stearoyl‐CoA desaturase ( SCD ) and acyl‐CoA synthetase long‐chain family member 3 ( ACSL3 ), and sensitizes cells to ferroptosis. Notably, combined treatment with the HDAC inhibitor SAHA and the ferroptosis inducer Erastin significantly enhances gemcitabine‐induced cytotoxicity in lipogenic PDAC cells. These findings uncover a previously unrecognized non‐catalytic function of TET3 in sustaining lipid metabolic reprogramming in PDAC. Targeting the TET3/GATA6 axis in combination with ferroptosis and epigenetic modulators offers a promising strategy to overcome therapeutic resistance in aggressive pancreatic cancer.

Cancer cells exploit altered metabolic pathways to dynamically regulate epigenetic methylation and thus promote tumorigenesis and metastasis. In various human cancers, such as lung adenocarcinoma, the level of a key cellular metabolite, S-adenosylmethionine (SAM), is prominently upregulated for RNA hypermethylation as the methyl donor. However, the specific mechanisms by which cancer cells produce SAM to sustain RNA methylation remain elusive. Here, we demonstrate that PRPS2, a phosphoribosyl pyrophosphate synthetase isoform involved in the first and rate-limiting step of the purine biosynthesis pathway, exhibits distinct oncogenic functionality in regulating RNA methylation, unlike its homolog PRPS1. PRPS2 utilizes four non-conserved key residues to bypass the typical ADP/GDP allosteric feedback inhibition, enabling sustained excess production of newly synthesized ATP. Moreover, PRPS2 stabilizes methionine adenosyltransferase 2 A (MAT2A) through direct interactions to positively stimulate ATP utilization and SAM synthesis for RNA m ⁶ A specific methylation via the WTAP/METTL3/METTL14 methyltransferase complex, thereby promoting lung tumorigenesis. Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities.

Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous noncoding RNAs in the nucleoplasm. Here we find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels. Specifically, ZCCHC8 depletion results in significant upregulation of nascent long noncoding RNAs (lncRNAs) containing G-quadruplex (G4) and U-Rich motifs (G4/U-Rich lncRNAs). The G4 motif binds to EZH2, blocking the chromatin recruitment of PRC2, while the U-Rich motif is specifically recognized by the NEXT complex for RNA exosome-mediated degradation. In tumor tissues with high ZCCHC8 expression in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patients, the NEXT complex excessively degrades nascent G4/U-Rich lncRNAs. Consequently, PRC2 core subunits are released and recruited to neighboring genomic loci, resulting in increased H3K27me3 levels and downregulation of adjacent genes, including tumor suppressors like SEMA5A and ARID1A. Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading nascent G4/U-Rich lncRNAs in cancer cells.