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

Cell Death Dis. 2023 Oct 11;14(10):670. doi: 10.1038/s41419-023-06210-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Hepatocellular* / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism
  • Humans
  • Liver Neoplasms* / genetics
  • Mice
  • Phosphoproteins / metabolism
  • RNA Splicing
  • Serine-Arginine Splicing Factors / metabolism
  • Ubiquitin-Specific Proteases / metabolism


  • SRSF6 protein, human
  • Serine-Arginine Splicing Factors
  • Phosphoproteins
  • HNRNPC protein, human
  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • USP39 protein, human
  • Ubiquitin-Specific Proteases
  • SRSF6 protein, mouse