Lu Chen, Liu Tianyu, Yimin E, Miao Lin, Yu Chunzhao, Zhang Jianping, Luo Xiagang
Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of General Surgery, Sir Run Run Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Biofactors. 2025 Jan-Feb;51(1):e2158. doi: 10.1002/biof.2158.
Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is the second leading cause of cancer mortality. FAM49B, a member of the FAM49 gene family, is a recently identified, evolutionarily conserved gene. Emerging studies indicate that FAM49B plays a role in various cancers, though its specific mechanism in CRC remains largely unexplored. In this study, we observed that FAM49B was abnormally expressed in CRC tissues and cell lines, with elevated expression correlating with poor patient prognosis. FAM49B knockdown markedly suppressed CRC cell proliferation by arresting the cell cycle and reducing cell migration and invasion. Single-cell RNA-seq (ScRNA-seq) analysis revealed that high FAM49B expression in malignant epithelial cell clusters was strongly linked to c-Myc oncogene activation. Further, FAM49B knockdown significantly reduced c-Myc expression by enhancing its K48 ubiquitination. We identified NEK9 as a direct interacting partner of FAM49B, with FAM49B knockdown inhibiting NEK9-Thr210 phosphorylation. Similarly, high NEK9 expression was linked to unfavorable prognosis in CRC. In FAM49B-overexpressing CRC cells, NEK9 knockdown significantly suppressed c-Myc expression, c-Myc-ser62 phosphorylation, and reduced cell proliferation, migration, and invasion. Thus, directly targeting the FAM49B/NEK9/c-Myc pathway presents a promising therapeutic approach for c-Myc positive CRC patients.
结直肠癌（CRC）是全球第三大常见癌症，也是癌症死亡的第二大主要原因。FAM49B是FAM49基因家族的成员，是最近发现的一个进化保守基因。新出现的研究表明，FAM49B在多种癌症中发挥作用，但其在CRC中的具体机制仍 largely unexplored。在本研究中，我们观察到FAM49B在CRC组织和细胞系中异常表达，其表达升高与患者预后不良相关。FAM49B敲低通过阻滞细胞周期、减少细胞迁移和侵袭，显著抑制CRC细胞增殖。单细胞RNA测序（ScRNA-seq）分析显示，恶性上皮细胞簇中高FAM49B表达与c-Myc癌基因激活密切相关。此外，FAM49B敲低通过增强其K48泛素化显著降低c-Myc表达。我们鉴定出NEK9是FAM49B的直接相互作用伙伴，FAM49B敲低抑制NEK9-Thr210磷酸化。同样，高NEK9表达与CRC患者的不良预后相关。在过表达FAM49B的CRC细胞中，敲低NEK9显著抑制c-Myc表达、c-Myc-ser62磷酸化，并减少细胞增殖、迁移和侵袭。因此，直接靶向FAM49B/NEK9/c-Myc通路为c-Myc阳性CRC患者提供了一种有前景的治疗方法。
