biostudies-literatureUnknown15(7)He YColorectal carcinogenesis and progression are associated with aberrant alternative splicing, yet its molecular mechanisms remain largely unexplored. Here, we find that Microrchidia family CW-type zinc finger 2 (MORC2) binds to RRM1 domain of RNA binding motif protein 39 (RBM39), and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, resulting in a splicing switch of cyclin-dependent kinase 5 regulatory subunit associated protein 2 (CDK5RAP2) L to CDK5RAP2 S. CDK5RAP2 S promotes invasion of colorectal cancer cells in vitro and metastasis in vivo. Mechanistically, CDK5RAP2 S specifically recruits the PHD finger protein 8 to promote Slug transcription by removing repressive histone marks at the Slug promoter. Moreover, CDK5RAP2 S, but not CDK5RAP2 L, is essential for the Cell death & disease530https://www.ebi.ac.uk/biostudies/studies/S-EPMC11269669biostudies-literatureMORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer.PMC11269669Liu XYang GHe YShao YLi TLi FGao YZhang LYuan GZhou ZfalseMORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer.Colorectal carcinogenesis and progression are associated with aberrant alternative splicing, yet its molecular mechanisms remain largely unexplored. Here, we find that Microrchidia family CW-type zinc finger 2 (MORC2) binds to RRM1 domain of RNA binding motif protein 39 (RBM39), and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, resulting in a splicing switch of cyclin-dependent kinase 5 regulatory subunit associated protein 2 (CDK5RAP2) L to CDK5RAP2 S. CDK5RAP2 S promotes invasion of colorectal cancer cells in vitro and metastasis in vivo. Mechanistically, CDK5RAP2 S specifically recruits the PHD finger protein 8 to promote Slug transcription by removing repressive histone marks at the Slug promoter. Moreover, CDK5RAP2 S, but not CDK5RAP2 L, is essential for the 2024-01-01T00:00:00Z2024 Jul2026-03-31T11:01:04.728Z2025-08-31T03:05:06.396ZS-EPMC112696693904855510.1038/s41419-024-06908-y