MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer - Article

Sep 21, 2026

Uploaded by Noah

Colorectal carcinogenesis and progression are linked to aberrant alternative splicing, but underlying molecular mechanisms are unclear. This study identifies MORC2 binding to RBM39 and RBM39 interaction with pre-CDK5RAP2 exon 32, creating a splicing switch from CDK5RAP2 L to CDK5RAP2 S. CDK5RAP2 S enhances invasion and metastasis, promotes Slug transcription via PHD finger protein 8 recruitment, and is required for MORC2- or RBM39-induced EMT. High MORC2, RBM39, and Slug levels correlate with metastasis and poor outcomes.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Colorectal cancer and alternative splicing

MORC2 in cancer and splicing

RBM39 in RNA splicing and cancer

CDK5RAP2 functions and colorectal cancer relevance

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN MORC2 regulates RBM39-mediated CDK5RAP2 alternative splicing to promote EMT and metastasis in colon cancer Yuxin He 1,2, Yangguang Shao 1,2 ✉ , Zhihui Zhou1, Tingting Li1, Yunling Gao 1, Xue Liu1, Gang Yuan1, Gaoxiang Yang 1, Lili Zhang 1 and Feng Li 1 ✉ © The Author(s) 2024 | | 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 promotion of epithelial-mesenchymal transition induced by MORC2 or RBM39 . Importantly, high protein levels of MORC2, RBM39 and Slug are strongly associated with metastasis and poor clinical outcomes of colorectal cancer patients. Taken together, our ﬁndings uncover a novel mechanism by which MORC2 promotes colorectal cancer metastasis, through RBM39-mediated pre-CDK5RAP2 alternative splicing and highlight the MORC2/RBM39/CDK5RAP2 axis as a potential | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | therapeutic target for colorectal cancer. | | | | | Cell Death and Disease (2024)15:530; [https://doi.org/10.1038/s41419-024-06908-y](https://doi.org/10.1038/s41419-024-06908-y) | | | | | | INTRODUCTION Colorectal cancer (CRC) is the third most diagnosed malignant disease and a major leading cause of cancer-related deaths in the world. In addition to gene mutations, aberrant pre-mRNA splicing becomes another major event that reﬂects the abnormalities of colorectal cancer cells [1]. Splicing factor-mediated alternative splicing (AS) has been demonstrated to be closely associated with colorectal cancer progression [2, 3]. For instance, SRSF6 regulates aberrant splicing of ZO-1 by directly binding to a motif in exon 23 of ZO-1, thereby promoting colorectal cancer progression [4]. Consequently, further investigation of alternative splicing events involved in the development and progression of colorectal cancer and their corresponding pathological features could contribute to the development of biomarkers and therapeutic targets for colorectal cancer. Microrchidia family CW-type zinc ﬁnger 2 (MORC2) is a member of the highly conserved MORC family protein. It plays an important role in epigenetic gene silencing, DNA repair, lipogenesis and glucose metabolism [5–11] . MORC2 is found to be up-regulated in multiple cancers, including breast cancer, gastric cancer, colorectal cancer and liver cancer. It promotes the growth, migration, invasion and metastasis of cancer cells [9, 12–19] . However, the effect and mechanism of MORC2 on alternative splicing in colon cancer are not understood. RNA binding motif protein 39 (RBM39) is an RNA-binding protein involved in transcriptional co-regulation and alternative splicing of pre-mRNAs [20, 21] . Several transcriptomic studies have also shown that RBM39 regulates alternative splicing of a variety of genes, such as genes related to the cell cycle [22–26] . RBM39-mediated alternative splicing is also involved in the carcinogenesis and progression of multiple cancers, including acute myeloid leukemia (AML), breast cancer, colorectal cancer and lung cancer [20, 21, 25, 27–29] . Indisulam (E7070), an anticancer sulfonamide, selectively recruits RBM39 to the CUL4-DCAF15 E3 ubiqui

FAQs

What splicing switch does MORC2/RBM39 control for CDK5RAP2?

MORC2 binds RBM39, which interacts with pre-CDK5RAP2 exon 32 to switch splicing from CDK5RAP2 L to CDK5RAP2 S.

How does CDK5RAP2 S promote EMT-related transcription?

CDK5RAP2 S recruits PHD finger protein 8 to remove repressive histone marks at the Slug promoter, thereby promoting Slug transcription.

Why is CDK5RAP2 S important for MORC2- or RBM39-induced EMT?

CDK5RAP2 S is essential for promoting epithelial-mesenchymal transition induced by MORC2 or RBM39, whereas CDK5RAP2 L is not sufficient.

Sep 21, 2026

Uploaded by Noah