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Human HCC crotonylation LC-MS/MS

ABSTRACT: Crotonylation, a crotonyl-CoA-based nonenzymatic protein translational modification, has effects on diverse biological processes such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases1-6. Crotonylation is also decreased in hepatocellular carcinomas (HCCs)7, but the mechanism remains unknown. Here, we described the role of glutaryl-CoA dehydrogenase (GCDH) on tumor suppression. GCDH depletion promoted hepatocellular carcinoma progression and metastasis in vitro and in vivo, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we used lysine crotonylome analysis and identified the pentose phosphate pathway and glycolysis-related genes PGD, TKT and ALDOC as GCDH-induced crotonylated targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production. The GCDH overexpression-induced pentose phosphate pathway blockade also stimulated peroxidation, synergizing with cell senescence and death modulators to induce these effects in GCDHhigh cells. These cells induced infiltration of immune cells by a paracrine senescence-associated secretory cell phenotype (SASP) to induce the self-clearance process. Meanwhile, GCDHlow cells recruited enough programmed cell death protein 1 positive (PD1+) targeted T cells for anti-PD1 therapy. Consistently, GCDH levels correlated with HCC prognoses and anti-tumor immunity outcomes, resulting in a tumor suppressive or vulnerable anti-PD1 therapeutic microenvironment in liver cancer.

ORGANISM(S): Homo Sapiens

SUBMITTER: Beicheng Sun

PROVIDER: PXD035465 | iProX | Thu Jul 21 00:00:00 BST 2022

REPOSITORIES: iProX

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