The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
Department of Pathology, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Oncogene. 2024 Nov;43(48):3532-3544. doi: 10.1038/s41388-024-03189-9. Epub 2024 Oct 13.
Oxaliplatin is the frontline chemotherapy drug for the treatment of colorectal cancer (CRC) and its insensitivity is a major limitation on therapeutic efficacy. Genomic instability is the prominent feature of CRC and is considered to correlate with response to treatments. However, the underlying mechanism of insensitivity to oxaliplatin (L-OHP) remains largely unclear. Herein, sequence similarity 135 family member B (FAM135B) is identified as a frequently mutated gene in CRC and is critical for CRC proliferation and impaired response to L-OHP by controlling SRSF1-mediated alternative splicing. Specifically, FAM135B promotes the nuclear translocation of SRSF1 by synergistically binding with SRPK1 and regulates SRSF1-mediated splicing of DNA repair genes. FAM135B-induced exon IV inclusion of FAAP20 mediates its binding with FACNA and enhances the functional integrity of the FA core complex, thereby activating the FA pathway and resulting in inter-strand crosslink (ICL) lesion repair and L-OHP insensitivity. These findings reveal that the FAM135B-SRSF1 axis-mediated splicing contributes to DNA repair and chemotherapeutic insensitivity in CRC. Targeting FAM135B represents a potential strategy for CRC treatment.
奥沙利铂是治疗结直肠癌（CRC）的一线化疗药物，其不敏感是治疗效果的主要限制因素。基因组不稳定性是 CRC 的突出特征，被认为与治疗反应相关。然而，奥沙利铂（L-OHP）不敏感的潜在机制在很大程度上仍不清楚。在此，序列相似性 135 家族成员 B（FAM135B）被鉴定为 CRC 中频繁突变的基因，通过控制 SRSF1 介导的可变剪接，对 CRC 的增殖和对 L-OHP 的反应受损至关重要。具体而言，FAM135B 通过与 SRPK1 协同结合促进 SRSF1 的核易位，并调节 SRSF1 对 DNA 修复基因的剪接。FAM135B 诱导 FAAP20 的外显子 IV 包含介导其与 FACNA 的结合，并增强 FA 核心复合物的功能完整性，从而激活 FA 途径，导致链间交联（ICL）损伤修复和 L-OHP 不敏感。这些发现揭示了 FAM135B-SRSF1 轴介导的剪接有助于 CRC 中的 DNA 修复和化疗不敏感。靶向 FAM135B 代表了 CRC 治疗的一种潜在策略。
