Gender dimorphism in hepatocarcinogenesis-DNA methylation modification regulated X-chromosome inactivation escape molecule XIST

Zhihui Dai; Sijie Wang; Xinggang Guo; Yuefan Wang; Haozan Yin; Jian Tan; Chenyang Mu; Shu-Han Sun; Hui Liu; Fu Yang

doi:10.1002/ctm2.1518

Gender dimorphism in hepatocarcinogenesis-DNA methylation modification regulated X-chromosome inactivation escape molecule XIST

Clin Transl Med. 2023 Dec;13(12):e1518. doi: 10.1002/ctm2.1518.

Authors

Zhihui Dai¹, Sijie Wang^{1

2}, Xinggang Guo³, Yuefan Wang^{1

3}, Haozan Yin¹, Jian Tan¹, Chenyang Mu^{1

2}, Shu-Han Sun¹, Hui Liu³, Fu Yang^{1

4

5}

Affiliations

¹ Department of Medical Genetics, Naval Medical University, Shanghai, China.
² School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China.
³ Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁴ Shanghai Key Laboratory of Medical Bioprotection, Shanghai, China.
⁵ Key Laboratory of Biological Defense, Ministry of Education, Shanghai, China.

Abstract

Background: Sex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood.

Methods: 5-Hydroxymethylcytosine (5hmC)-Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)-administered Tet2^-/- female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software.

Results: The results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence-free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN-administered Tet2^-/- mice developed more tumours than controls in female mice.

Conclusions: Our study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis.

Highlights: XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2-YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.

Keywords: DNA methylation; TET2; XIST; hepatocellular carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / chemically induced
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Chromosomes / metabolism
DNA Methylation / genetics
Female
Humans
Liver Neoplasms* / metabolism
Male
Mice
Sex Characteristics

Substances

XIST non-coding RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding