2-Hydroxyisobutyrylation of SRSF9 Regulates CD44 Alternative Splicing to Promote Colorectal Cancer Liver Metastasis.

Authors

Mengrou Zhang, Jinming Song, Shuhui Yu, Huolian Liu, Zhun Li, Tiantian Nie, Jiali Qi, Saiqi He, Chuanjie Zhang, Xunhua Liu, Su Yao, Wen Ni, Jianming Li

Published in

Cancer letters. Pages 218900. Oct 17, 2026. Epub Oct 17, 2026.

Abstract

Colorectal cancer liver metastasis (CRLM) remains a major cause of cancer mortality, yet the metabolic mechanisms that remodel metastatic RNA-splicing programs are poorly defined. Here, integrated quantitative proteomics and lysine 2-hydroxyisobutyrylation (Khib) proteomics of patient-matched normal mucosa, primary CRCs, and liver metastases revealed a progressive increase in global Khib, with enrichment on RNA-splicing proteins. Serine/arginine-rich splicing factor 9 (SRSF9) emerged as a Khib-modified splicing factor whose expression and K155 Khib levels increased from normal tissue to primary tumors and liver metastases. Gain and loss of function studies in CRC cell lines, patient-derived organoids, subcutaneous xenografts, and splenic injection liver metastasis models showed that SRSF9 promotes proliferation, invasion, tumor growth, and liver colonization. Mechanistically, K155 Khib stabilized SRSF9 protein; the K155R mutation accelerated degradation and abolished SRSF9-driven malignant phenotypes. KAT7 and SIRT6 act as regulators of Khib modification, which positively and negatively modulate the K155 Khib modification of SRSF9, respectively. SRSF9 bound CD44 pre-mRNA through its RRM1 domain and promoted alternative splicing toward the oncogenic CD44V8-10 isoform, which was elevated in patient tumors and metastases and rescued the impaired proliferation and metastatic capacity caused by SRSF9 loss. Finally, a CD44V8-10-targeting antisense oligonucleotide suppressed CRC growth and liver metastasis in preclinical models. These findings define a KAT7/SIRT6-regulated Khib-SRSF9-CD44V8-10 axis that couples metabolic acylation to metastatic splicing and nominate CD44V8-10 as a therapeutic vulnerability in CRC liver metastasis.

PMID:
42892521
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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