USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC
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...
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Nature Publishing Group
2023-10-01
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Series: | Cell Death and Disease |
Online Access: | https://doi.org/10.1038/s41419-023-06210-3 |
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author | 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 |
author_facet | 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 |
author_sort | Jingyi Zheng |
collection | DOAJ |
description | 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. |
first_indexed | 2024-03-11T18:20:45Z |
format | Article |
id | doaj.art-0db94b0631834832aca8606a3f0a42f2 |
institution | Directory Open Access Journal |
issn | 2041-4889 |
language | English |
last_indexed | 2024-03-11T18:20:45Z |
publishDate | 2023-10-01 |
publisher | Nature Publishing Group |
record_format | Article |
series | Cell Death and Disease |
spelling | doaj.art-0db94b0631834832aca8606a3f0a42f22023-10-15T11:30:09ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011410.1038/s41419-023-06210-3USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPCJingyi Zheng0Shasha Wu1Mao Tang2Shaoyan Xi3Yanchen Wang4Jun Ren5Hao Luo6Pengchao Hu7Liangzhan Sun8Yuyang Du9Hui Yang10Fenfen Wang11Han Gao12Ziwei Dai13Xijun Ou14Yan Li15Department of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Pathology, Sun Yat-Sen University Cancer CenterDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyDepartment of Biology, School of Life Sciences, Southern University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41419-023-06210-3 |
spellingShingle | 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 USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC Cell Death and Disease |
title | USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC |
title_full | USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC |
title_fullStr | USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC |
title_full_unstemmed | USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC |
title_short | USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC |
title_sort | usp39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with srsf6 hnrnpc |
url | https://doi.org/10.1038/s41419-023-06210-3 |
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