Feng Wenxin, Liu Ningyuan, Liu Changwei, Rao Hanyu, Chen Zhuo, Zhang Wei, Xu Yue, Aji Rebiguli, Wang Ziyi, Gao Wei-Qiang, Li Li
State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Oncogene. 2025 Jul 22. doi: 10.1038/s41388-025-03505-x.
Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. NSD2 is an H3K36-specific di-methyltransferase that has been reported to participate in diverse biological processes and human tumors. However, its role in RCC remains unclear. Here, we found that NSD2 is highly expressed in RCC, which is associated with poor survival in RCC patients. NSD2 facilitates the transition from Myc-induced polycystic kidney disease to tubulocystic renal cell carcinoma (TCRCC), which is a rare RCC subtype with distinctive clinicopathologic and genetic characterizations. The mice with kidney-specific overexpression of MYC and NSD2 (KMN) display severe cyst burden at only 6 weeks of age, and develop into TCRCC at 12 weeks of age. Mechanistically, NSD2 transcriptionally upregulates the expressions of integrins (Itga4 and Itga11), to further activate the FAK/AKT pathway. In addition, we found that NSD2 enhances cell proliferation on the stiff matrix of PEGDA hydrogel. Moreover, inhibition of FAK signaling relieves the symptoms of KMN mice, and significantly rescues the enhanced cell proliferation caused by NSD2 overexpression in vitro. Together, our findings highlight an epigenetic mechanism by which NSD2 regulates TCRCC tumorigenesis through the integrin/FAK/AKT pathway. This study may also pave the way for the development of targeted, patient-tailored therapies for TCRCC patients with NSD2 amplification or high expression.
肾细胞癌（RCC）是泌尿系统中最常见的恶性肿瘤之一。NSD2是一种H3K36特异性二甲基转移酶，据报道它参与多种生物学过程和人类肿瘤。然而，其在RCC中的作用仍不清楚。在此，我们发现NSD2在RCC中高表达，这与RCC患者的不良生存相关。NSD2促进从Myc诱导的多囊肾病向肾小管囊性肾细胞癌（TCRCC）的转变，TCRCC是一种罕见的RCC亚型，具有独特的临床病理和基因特征。肾脏特异性过表达MYC和NSD2的小鼠（KMN）在仅6周龄时就表现出严重的囊肿负担，并在12周龄时发展为TCRCC。机制上，NSD2转录上调整合素（Itga4和Itga11）的表达，以进一步激活FAK/AKT途径。此外，我们发现NSD2增强了在PEGDA水凝胶刚性基质上的细胞增殖。而且，抑制FAK信号可缓解KMN小鼠的症状，并显著挽救体外由NSD2过表达引起的细胞增殖增强。总之，我们的研究结果突出了一种表观遗传机制，即NSD2通过整合素/FAK/AKT途径调节TCRCC的肿瘤发生。这项研究也可能为针对NSD2扩增或高表达的TCRCC患者开发靶向、个性化治疗方法铺平道路。
