Wang Lingfang, Zhang Jian, Su Yingfeng, Maimaitiyiming Yasen, Yang Siqi, Shen Zhangjin, Lin Shitong, Shen Shizhen, Zhan Guankai, Wang Fenfen, Hsu Chih-Hung, Cheng Xiaodong
Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Women's Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Front Oncol. 2022 Feb 25;12:786266. doi: 10.3389/fonc.2022.786266. eCollection 2022.
RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (mC) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of mC. Gynecologic cancers are malignancies starting from women's reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to mC methylation on keratin 13 () transcripts, and methylated transcripts would be recognized and stabilized by an mC reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent mC-YBX1-KRT13 oncogenic regulatory pathway.
RNA甲基化最近已成为表观遗传修饰的一个重要类别，它在各种癌症中发挥着多种生理病理作用。最近的研究证实哺乳动物mRNA上存在5-甲基胞嘧啶（mC）修饰，主要由NOP2 / Sun RNA甲基转移酶家族成员2（NSUN2）修饰，但关于mC的潜在功能知之甚少。妇科癌症是起源于女性生殖器官的恶性肿瘤。妇科癌症的流行导致了巨大的经济负担和公共卫生问题。在本研究中，我们调查了NSUN2在常见妇科癌症（包括宫颈癌、卵巢癌和子宫内膜癌）中的潜在生物学功能。值得注意的是，发现了不同的情况。NSUN2的水平在子宫内膜癌中未显示出变化，而在卵巢癌中，上调的NSUN2的缺失并未降低癌细胞的致癌作用，这表明上调的NSUN2可能是一种偶然效应。相反，NSUN2在宫颈癌的肿瘤发生中起作用；上调的NSUN2的缺失显著抑制了癌细胞的迁移和侵袭，并且只有野生型而非催化失活的NSUN2挽救了癌细胞的这些恶性表型。从机制上讲，NSUN2通过导致角蛋白13（KRT13）转录本上的mC甲基化来促进迁移和侵袭，并且甲基化的转录本将被mC阅读器Y盒结合蛋白1（YBX1）识别并稳定。总的来说，这些结果不仅展示了人类恶性肿瘤之间多样性的本质，还证明了一种新的NSUN2依赖性mC-YBX1-KRT13致癌调节途径。
