Das, Tanuza Lee, Eun-Young You, Hye Jin Kim, Eunice EunKyeong Song, Eun Joo 2024-01-19T13:01:41Z 2024-01-19T13:01:41Z 2022-02-17 2022-01 2058-7716 https://pubs.kist.re.kr/handle/201004/115850 The deubiquitinating enzyme USP15 is implicated in several human cancers by regulating different cellular processes, including splicing regulation. However, the underlying molecular mechanisms of its functional relevance and the successive roles in enhanced tumorigenesis remain ambiguous. Here, we found that USP15 and its close paralog USP4 are overexpressed and facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1. Depletion of USP15 and USP4 impair SRSF1 splicing characterized by the replacement of exon 4 with non-coding intron sequences retained at its C-terminus, resulting in an alternative isoform SRSF1-3. We observed an increased endogenous expression of SRSF1 in lung cancer cells as well, and its overexpression significantly enhanced cancer cell phenotype and rescued the depletion effect of USP15 and USP4. However, the alternatively spliced isoform SRSF1-3 was deficient in such aspects for its premature degradation through nonsense-mediated mRNA decay. The increased USP15 expression contributes to the lung adenocarcinoma (LUAD) development and shows significantly lower disease-specific survival of patients with USP15 alteration. In short, we identified USP15 and USP4 as key regulators of SRSF1 alternative splicing with altered functions, which may represent the novel prognostic biomarker as well as a potential target for LUAD. English Nature Publishing Group USP15 and USP4 facilitate lung cancer cell proliferation by regulating the alternative splicing of SRSF1 Article 10.1038/s41420-022-00820-0 1 Cell Death Discovery, v.8, no.1 Cell Death Discovery 8 1 Y scie scopus 000742360100001 2-s2.0-85123113570 Cell Biology Cell Biology Article PRE-MESSENGER-RNA SF2/ASF EXPRESSION SURVIVAL ABERRANT PROTEIN FAMILY GENE UBIQUITINATION ONCOPROTEIN