Li Xukun, Fan Dandan, Li Yong, Yuan Jian, Sun Wanyuan, Zhu Qinghao, Qi Ling, Wu Xueling, Cai Jiahui, Gong Tongyang, Zhao Ning, Su Jianzhong, Liu Zhihua, Chen Hongyan
The State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.
Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academic of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, P. R. China.
Adv Sci (Weinh). 2025 May;12(20):e2413508. doi: 10.1002/advs.202413508. Epub 2025 Apr 30.
DNA methylation regulators play critical roles in modulating oncogenic driver genes in cancers. However, the precise mechanisms through which these DNA methylation regulators influence oncogenesis and clinical therapy have yet to be fully elucidated. This study reveals that hypermethylation of under-methylated regions (UMRs) within gene bodies is involved in the activation of oncogenic homeobox genes, particularly NKX2-5 and LHX1, in esophageal squamous cell carcinoma (ESCC). Mechanistically, NKX2-5 and LHX1 synergistically bind to the promoter region of UHRF1, thereby augmenting its transcription. In turn, UHRF1 orchestrates the recruitment of DNMT1/DNMT3A, alongside NKX2-5 and LHX1, to the UMRs of these genes, thereby increasing DNA methylation levels and their expression. This intricate interplay forms a positive transcriptional feedback loop between NKX2-5/LHX1 and UHRF1, thus promoting the overexpression of all three genes and ultimately facilitating tumor growth. Notably, concurrent inhibition of UHRF1 and DNMTs impedes tumor growth by suppressing NKX2-5 and LHX1 expression. Overall, this study identifies a positive feedback regulatory circuitry underlying the UMR hypermethylation-mediated activation of oncogenic drivers in ESCC and proposes a promising therapeutic strategy for ESCC patients.
DNA甲基化调节因子在调控癌症中的致癌驱动基因方面发挥着关键作用。然而，这些DNA甲基化调节因子影响肿瘤发生和临床治疗的精确机制尚未完全阐明。本研究揭示，基因体内低甲基化区域（UMRs）的高甲基化参与了食管鳞状细胞癌（ESCC）中致癌同源框基因的激活，特别是NKX2-5和LHX1。从机制上讲，NKX2-5和LHX1协同结合到UHRF1的启动子区域，从而增强其转录。反过来，UHRF1协同NKX2-5和LHX1将DNMT1/DNMT3A招募到这些基因的UMRs，从而增加DNA甲基化水平及其表达。这种复杂的相互作用在NKX2-5/LHX1和UHRF1之间形成了一个正转录反馈环，从而促进这三个基因的过表达并最终促进肿瘤生长。值得注意的是，同时抑制UHRF1和DNA甲基转移酶通过抑制NKX2-5和LHX1的表达来阻碍肿瘤生长。总体而言，本研究确定了ESCC中UMR高甲基化介导的致癌驱动基因激活背后的正反馈调节回路，并为ESCC患者提出了一种有前景的治疗策略。
