Abstract
Abstract Methionine adenosyltransferase 2A (MAT2A) is an essential enzyme responsible for biosynthesis of S-adenosylmethionine, a methyl-group donor of various methyltransferases. Pancreatic ductal adenocarcinoma PDAC is characterized by severe hypoxia and upregulates autophagy and lysosomal biogenesis to enhance nutrient recycling and stress resistance. Here we show that a subset of MAT2A is targeted via the autophagy pathway for degradation by the lysosome under normoxia in PDAC cells, but is subsequently protected against degradation under hypoxia. Mechanistically, we show that the autophagy cargo receptor SQSTM1 (p62) binds to MAT2A in a ubiquitin-dependent manner under normoxia to regulate its autophagic capture. Under hypoxic conditions, stabilized MAT2A potentially facilities increased flux of methionine towards increased SAM, suggesting that protection of MAT2A against lysosomal degradation might enable alterations in methionine metabolism that drive epigenetic and metabolic adaptation to stress. Citation Format: Yang Yang, Wenping Wang, Gilles Rademaker, Mirunalini Ravichandran, Jingjie Hu, Alexander Li, Joseph D. Mancias, Jessie Yanxiang Guo, Rushika M. Perera. Autophagy regulates MAT2A in response to hypoxia in pancreatic cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C053.
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