Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong, China.
Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518000, Guangdong, China.
Int J Biol Sci. 2022 May 16;18(9):3621-3635. doi: 10.7150/ijbs.70972. eCollection 2022.
The poor sensitivity of clear cell renal cell carcinoma (ccRCC) to conventional chemotherapy and radiotherapy makes its treatment challenging. The Ndc80 kinetochore complex component (NUF2) is involved in the development and progression of several cancers. However, its role in ccRCC remains unclear. In this study, we investigated the biological functions and underlying mechanism of NUF2 in ccRCC. We found that NUF2 expression was increased in ccRCC and associated with poor prognosis. Altering NUF2 level affected cell proliferation, migration, and invasion. Moreover, NUF2 acted as a potential oncogene to promote the progression of ccRCC through epigenetic activation of high-mobility group AT-hook 2 (HMGA2) transcription by suppressing lysine demethylase 2A expression and affecting its occupancy on the promoter region to regulate histone H3 lysine 36 di-methylation modification. In addition, Kaplan-Meier and multivariate analysis revealed that patients whose NUF2 and HMGA2 were both elevated showed the shortest survival; and the number of upregulated markers acted as an independent predictor to evaluate survival probability. Thus, our results demonstrate that NUF2 promotes ccRCC progression, at least partly by epigenetically regulating HMGA2 transcription, and that the NUF2-HMGA2 axis could be an ideal therapeutic target and a promising prognostic indicator for ccRCC.
透明细胞肾细胞癌（ccRCC）对传统化疗和放疗的敏感性较差，使其治疗具有挑战性。Ndc80 着丝粒复合物成分（NUF2）参与了几种癌症的发生和发展。然而，其在 ccRCC 中的作用尚不清楚。在这项研究中，我们研究了 NUF2 在 ccRCC 中的生物学功能和潜在机制。我们发现 NUF2 在 ccRCC 中表达增加，并与预后不良相关。改变 NUF2 水平会影响细胞增殖、迁移和侵袭。此外，NUF2 通过抑制赖氨酸去甲基化酶 2A 的表达并影响其在启动子区域的占据来调节组蛋白 H3 赖氨酸 36 二甲基化修饰，从而作为潜在的癌基因促进 ccRCC 的进展，以表观遗传激活高迁移率族 AT 盒 2（HMGA2）转录。此外，Kaplan-Meier 和多变量分析显示，NUF2 和 HMGA2 均升高的患者的生存时间最短；上调标志物的数量可作为独立预测因子来评估生存概率。因此，我们的研究结果表明，NUF2 通过表观遗传调控 HMGA2 转录促进 ccRCC 的进展，NUF2-HMGA2 轴可能是 ccRCC 的理想治疗靶点和有前途的预后标志物。
