UBE3A-mediated mH2A1 Ubiquitination activates TERT transcription to promote senescence resistance in pancreatic cancer

Abstract Pancreatic cancer is a highly aggressive tumor with a poor prognosis. The ubiquitin-proteasome system is crucial in maintaining protein homeostasis and regulating cellular senescence, thereby influencing tumorigenesis and progression; however, the specific mechanisms underlying this process remain unclear. Ubiquitin protein ligase E3A (UBE3A) is associated with various tumors; however, its potential role in pancreatic cancer warrants further investigation. The effects of UBE3A on cellular senescence were evaluated through in vitro and in vivo experiments, including SA-β-gal staining, EdU assays, detection of senescence-associated markers, and the establishment of subcutaneous xenograft and liver metastasis models. Mechanistic studies utilized Ub-MS, IP-MS, ChIP-seq, and RNA-seq to explore downstream pathways, followed by validation through ubiquitination assays, ChIP-qPCR, and dual-luciferase reporter assays. Our results showed that UBE3A was significantly upregulated in pancreatic cancer tissues and correlated with poor patient outcomes. Functional studies have demonstrated that UBE3A inhibits cellular senescence in pancreatic cancer cells, thereby promoting tumor proliferation and metastasis. Mechanistically, the histone variant macroH2A1 (mH2A1) recruits EZH2 to mediate H3K27me3 modification, repressing Telomerase reverse transcriptase (TERT) transcription. UBE3A interacts with mH2A1 through its N-terminal domain, leading to K48-linked polyubiquitination at the K167 residue, which accelerates mH2A1 degradation and upregulates TERT, enhancing the anti-senescence capacity of pancreatic cancer cells. Inhibition of UBE3A combined with the senolytic agent ABT‑263 induced apoptosis and inhibited tumor growth. The UBE3A/mH2A1/TERT axis enhances the anti-senescence capacity of pancreatic cancer cells and drives malignant progression, suggesting that UBE3A may serve as a novel therapeutic target for pancreatic cancer.