Open Access
ARTICLE
Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer
YOULIN TUO, XUBAO LIU*
Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
* Corresponding Author: XUBAO LIU. Email:
(This article belongs to this Special Issue: )
BIOCELL 2023, 47(2), 319-328. https://doi.org/10.32604/biocell.2023.025250
Received 01 July 2022; Accepted 31 August 2022; Issue published 18 November 2022
Abstract
Retinoic acid receptor responder 3 (RARRES3) has been characterized as a tumor suppressor in multiple types of cancer. This study aimed to examine the expression profile of
RARRES3 across the PAM50 subtypes of breast cancer. The DNA methylation status of
RARRES3 was checked in the basal-like subtype, and the underlying mechanisms of its dysregulation were explored. RNA-sequencing (seq) and methylation data from The Cancer Genome Atlas were used for in-silico analysis. Basal-like representative SUM149 and MDA-MB-468 cell lines were used for
in vitro and
in vivo studies. Compared to tumor-adjacent normal tissues, only the basal-like tumor tissues had significantly downregulated
RARRES3 expression. The methylation level of four CpG sites in the promoter region showed a strong negative correlation with
RARRES3 expression. The gene coding for DNA methyltransferase 3A (
DNMT3A) had consistent positive correlations with the methylation of the CpG sites. Chromatin Immunoprecipitation-quantitative polymerase chain-reaction and bisulfite sequencing PCR showed that DNMT3A could bind to the promoter region of
RARRES3 and promote methylation of the CpG sites within the region.
DNMT3A knockdown significantly restored
RARRES3 expression at the mRNA and protein level in the two cell lines. CCK-8, colony formation, and flow cytometric analysis showed that
RARRES3 overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the
DNMT3A overexpression-induced activation of ERK1/2 and PI3K/AKT signaling. In summary, this study revealed that DNMT3A enhances promoter methylation of the
RARRES3 gene and suppresses its transcription in basal-like breast cancer. The DNMT3A-RARRES3 signaling pathway might be a potential target for the treatment of this tumor subtype.
Keywords
Cite This Article
TUO, Y., LIU, X. (2023). Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer.
BIOCELL, 47(2), 319–328.