@Article{biocell.2023.025250,
AUTHOR = {YOULIN TUO, XUBAO LIU},
TITLE = {Methyltransferase 3A-mediated promoter methylation represses retinoic acid receptor responder 3 expression in basal-like breast cancer},
JOURNAL = {BIOCELL},
VOLUME = {47},
YEAR = {2023},
NUMBER = {2},
PAGES = {319--328},
URL = {http://www.techscience.com/biocell/v47n2/50471},
ISSN = {1667-5746},
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 <i>RARRES3</i> across the PAM50 subtypes of breast cancer. The DNA methylation status of <i>RARRES3</i> 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 <i>in vitro</i> and <i>in vivo</i> studies. Compared to tumor-adjacent normal tissues, only the basal-like tumor tissues had significantly downregulated <i>RARRES3</i> expression. The methylation level of four CpG sites in the promoter region showed a strong negative correlation with <i>RARRES3</i> expression. The gene coding for DNA methyltransferase 3A (<i>DNMT3A</i>) 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 <i>RARRES3</i> and promote methylation of the CpG sites within the region. <i>DNMT3A</i> knockdown significantly restored <i>RARRES3</i> expression at the mRNA and protein level in the two cell lines. CCK-8, colony formation, and flow cytometric analysis showed that <i>RARRES3</i> overexpression attenuated the growth-promoting effects of DNMT3A overexpression and also weakened the <i>DNMT3A</i> overexpression-induced activation of ERK1/2 and PI3K/AKT signaling. In summary, this study revealed that DNMT3A enhances promoter methylation of the <i>RARRES3</i> 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.},
DOI = {10.32604/biocell.2023.025250}
}