USP39 Promotes Hepatocellular Carcinogenesis Through Regulating Alternative Splicing in Cooperation with SRSF6/HNRNPC

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2023 Oct 11

PMID 37821439

Authors

Jingyi Zheng

Shasha Wu

Mao Tang

Shaoyan Xi

Yanchen Wang

Jun Ren

Hao Luo

Pengchao Hu

Liangzhan Sun

Yuyang Du

Hui Yang

Fenfen Wang

Han Gao

Ziwei Dai

Xijun Ou

Yan Li

Affiliations

Soon will be listed here.

Abstract

Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1 and U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remains largely elusive. We observed that hepatocyte-specific overexpression of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection in transgenic mice. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represented a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy.

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