Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.

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

doi:10.3389/fonc.2022.786266

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.

Highlights

Due to the single-stranded nature and relatively flexible structure, RNA carries a diverse array of post-transcriptional chemical modifications, including N6methyladenosine (m6A), N1-methyladenosine (m1A), 5methylcytosine (m5C), 5-hydroxymethylcytosine, and 2′-O-methylation (Nm) [1]
The results from GEO datasets showed no statistically significant difference of NSUN2 expression in uterine corpus endometrial cancer (UCEC) (Figure 1A), while NSUN2 is significantly upregulated in ovarian cancer (OV) and cervical squamous cell carcinoma (CESC) (Figures 1B, C)
These findings suggest that NSUN2 likely contributes to the carcinogenesis of ovarian cancer and cervical cancer but not endometrial cancer

Summary

Introduction

Due to the single-stranded nature and relatively flexible structure, RNA carries a diverse array of post-transcriptional chemical modifications (over 160), including N6methyladenosine (m6A), N1-methyladenosine (m1A), 5methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), and 2′-O-methylation (Nm) [1]. Recent studies have well unveiled the functions of m6A modification in numerous biological processes [3–5], but little is known about the functions of m5C modification. NSUN2 is the most well-characterized m5C methyltransferase with robust catalytic activity for mRNA methylation [7]. It is reported that two residues, named releasing (cysteine 271) and catalytic (cysteine 321) sites, play key roles in the enzymatic activity of NSUN2. NSUN2mediated regulation of certain mRNAs has been reported to take part in multiple biological processes, such as stress response [10], regulation of mitotic spindle stability [11], and cell proliferation [12]. Several studies have reported high expression of NSUN2 in certain types of neoplasms including breast cancer, colorectal cancer, and lung cancer [13, 14]. Little is known about how aberrantly expressed NSUN2 contributes to pathogenesis and development of cancer

Methods

Results

Conclusion