Cheng Xi-Xi, Lin Guo-Wang, Zhou Ya-Qing, Li Yi-Qi, He Shuai, Liu Yang, Zeng Yan-Ni, Guo Yun-Miao, Liu Shu-Qiang, Peng Wan, Wei Pan-Pan, Luo Chun-Ling, Bei Jin-Xin
State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China; Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China.
J Genet Genomics. 2025 Apr;52(4):559-569. doi: 10.1016/j.jgg.2024.12.008. Epub 2024 Dec 18.
Various genetic association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with nasopharyngeal carcinoma (NPC) risk. However, these studies have predominantly focused on common variants, leaving the contribution of rare variants to the "missing heritability" largely unexplored. Here, we integrate genotyping data from 3925 NPC cases and 15,048 healthy controls to identify a rare SNP, rs141121474, resulting in a Glu510Lys mutation in KLHDC4 gene linked to increased NPC risk. Subsequent analyses reveal that KLHDC4 is highly expressed in NPC and correlates with poorer prognosis. Functional characterizations demonstrate that KLHDC4 acts as an oncogene in NPC cells, enhancing their migratory and metastatic capabilities, with these effects being further augmented by the Glu510Lys mutation. Mechanistically, the Glu510Lys mutant exhibits increased interaction with Vimentin compared to the wild-type KLHDC4 (KLHDC4-WT), leading to elevated Vimentin protein stability and modulation of the epithelial-mesenchymal transition process, thereby promoting tumor metastasis. Moreover, Vimentin knockdown significantly mitigates the oncogenic effects induced by overexpression of both KLHDC4-WT and the Glu510Lys variant. Collectively, our findings highlight the critical role of the rare KLHDC4 variant rs141121474 in NPC progression and propose its potential as a diagnostic and therapeutic target for NPC patients.
多项基因关联研究已鉴定出众多与鼻咽癌（NPC）风险相关的单核苷酸多态性（SNP）。然而，这些研究主要集中在常见变异上，罕见变异对“缺失遗传度”的贡献在很大程度上尚未得到探索。在此，我们整合了3925例NPC病例和15048例健康对照的基因分型数据，以鉴定出一种罕见的SNP，即rs141121474，其导致KLHDC4基因发生Glu510Lys突变，与NPC风险增加相关。后续分析表明，KLHDC4在NPC中高表达且与较差的预后相关。功能表征显示，KLHDC4在NPC细胞中作为癌基因发挥作用，增强其迁移和转移能力，而Glu510Lys突变进一步增强了这些作用。从机制上讲，与野生型KLHDC4（KLHDC4-WT）相比，Glu510Lys突变体与波形蛋白的相互作用增加，导致波形蛋白蛋白稳定性升高，并调节上皮-间质转化过程，从而促进肿瘤转移。此外，敲低波形蛋白可显著减轻由KLHDC4-WT和Glu510Lys变体过表达诱导的致癌作用。总的来说，我们的研究结果突出了罕见的KLHDC4变体rs141121474在NPC进展中的关键作用，并提出其作为NPC患者诊断和治疗靶点的潜力。
