Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers

Lingfang Wang; Jian Zhang; Yingfeng Su; Yasen Maimaitiyiming; Siqi Yang; Zhangjin Shen; Shitong Lin; Shizhen Shen; Guankai Zhan; Fenfen Wang; Chih-Hung Hsu; Xiaodong Cheng

doi:10.3389/fonc.2022.786266

Distinct Roles of m⁵C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers

Front Oncol. 2022 Feb 25:12:786266. doi: 10.3389/fonc.2022.786266. eCollection 2022.

Authors

Lingfang Wang^{1

2}, Jian Zhang², Yingfeng Su², Yasen Maimaitiyiming^{2

3}, Siqi Yang⁴, Zhangjin Shen¹, Shitong Lin⁵, Shizhen Shen¹, Guankai Zhan², Fenfen Wang¹, Chih-Hung Hsu², Xiaodong Cheng¹

Affiliations

¹ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Women's Hospital, Institute of Genetics and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Hematology of First Affiliated Hospital and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Clinical Research Center, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁵ Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

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 (m⁵C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m⁵C. 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 m⁵C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m⁵C 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 m⁵C-YBX1-KRT13 oncogenic regulatory pathway.

Keywords: KRT13; NSUN2; YBX1; cervical cancer; endometrial cancer; m5C; ovarian cancer.