A rare <i>KLHDC4</i> variant Glu510Lys is associated with genetic susceptibility and promotes tumor metastasis in nasopharyngeal carcinoma

Xi-Xi Cheng; Guo-Wang Lin; Ya-Qing Zhou; Yi-Qi Li; Shuai He; Yang Liu; Yan-Ni Zeng; Yun-Miao Guo; Shu-Qiang Liu; Wan Peng; Pan-Pan Wei; Chun-Ling Luo; Jin-Xin Bei

doi:10.1016/j.jgg.2024.12.008

Volume 52 Issue 4

Apr. 2025

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Article Navigation > Journal of Genetics and Genomics > 2025 > 52(4): 559-569

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A rare KLHDC4 variant Glu510Lys is associated with genetic susceptibility and promotes tumor metastasis in nasopharyngeal carcinoma

doi: 10.1016/j.jgg.2024.12.008

a. 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;
b. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China;
c. Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, China;
d. Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China;
e. Zhanjiang Institute of Clinical Medicine, Central People's Hospital of Zhanjiang, Guangdong Medical University Zhanjiang Central Hospital, Zhanjiang, Guangdong 524045, China;
f. Sun Yat-sen University Institute of Advanced Studies Hong Kong, Science Park, Hong Kong SAR, China;
g. Department of Medical Oncology, National Cancer Centre Singapore, Singapore

Funds:

This work was supported by the National Natural Science Foundation (82261160657, 82102490, and 81572781), the Guangdong Basic and Applied Basic Research Foundation (2024A1515013061), the Sci-Tech Project Foundation of Guangzhou City (2023A04J2141), Chang Jiang Scholars Program (J.-X.B.), the Hong Kong Research Grant Council (RGC) Theme-based Research Scheme Funds (T12-703/22-R and T12-703/23-N).

Received Date: 2024-09-05
Accepted Date: 2024-12-09
Rev Recd Date: 2024-12-09

Available Online: 2025-07-11

Publish Date: 2024-12-18

Abstract

Abstract

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.
- Nasopharyngeal carcinoma,
- Genetic susceptibility,
- Single nucleotide polymorphism,
- KLHDC4,
- Vimentin,
- Tumor metastasis

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