Dataset Information

The spliceosome factor USP39 promotes hepatocellular carcinoma malignancy through regulating mRNA splicing

ABSTRACT: Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Nonetheless, the relevant targets and mechanisms remain elusive in hepatocellular carcinoma (HCC). Here, we reported that overexpression of Ubiquitin-specific protease 39 (USP39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is associated with poor clinical outcomes and proliferative signaling. Functionally, hepatocyte-specific USP39 knockin mice exhibited enhanced hepatocarcinogenesis. In vitro, USP39 promoted HCC cell proliferation and cell cycle progression in a spliceosome-dependent manner. Transcriptomic analysis revealed that USP39 depletion led to comprehensively impaired constitutive splicing and intriguingly, selective AS of hundreds of genes. USP39-mediated splicing switch of KANK2-S to KANK2-L increased the tumorigenic potential of HCC cells through accelerating KANK2 translation. Mechanistically, USP39 modulates exon inclusion/exclusion via interaction with SRSF6 or hnRNPC in a position-dependent manner. These findings highlight a role for USP39 as a splicing regulator in HCC biology and establishing its position-dependent splicing model.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Adult Hepatocellular Carcinoma

SUBMITTER: Yan Li

LAB HEAD: Yan Li

PROVIDER: PXD035928 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC.

Zheng Jingyi J Wu Shasha S Tang Mao M Xi Shaoyan S Wang Yanchen Y Ren Jun J Luo Hao H Hu Pengchao P Sun Liangzhan L Du Yuyang Y Yang Hui H Wang Fenfen F Gao Han H Dai Ziwei Z Ou Xijun X Li Yan Y

Cell death & disease 20231011 10

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 tran ...[more]

PMID: 37821439

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