Open AccessErbB2 signaling epigenetically suppresses micro RNA ‐205 transcription via Ras/Raf/ MEK / ERK pathway in breast cancer
Author(s) -
Hasegawa Takuya,
Adachi Ryohei,
Iwakata Hitoshi,
Takeno Takayoshi,
Sato Koji,
Sakamaki Toshiyuki
Publication year - 2017
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12256
Subject(s) - mapk/erk pathway , mek inhibitor , kinase , cancer research , microbiology and biotechnology , biology , dna methylation , chemistry , gene expression , gene , biochemistry
We previously reported that micro RNA ‐205 (miR‐205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR‐205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR‐205 downregulation. In ErbB2‐overexpressing breast epithelial cells, miR‐205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD 98059, Raf‐1 inhibitor ZM ‐336372, and ERK inhibitor SCH 772984, but PI 3K inhibitor LY 294002 and p38 MAPK inhibitor SB 203580 had no effect. We established breast epithelial cells overexpressing Raf CAAX , a constitutively active form of Raf‐1, and showed that overexpression of Raf CAAX dramatically reduced miR‐205 expression. In Raf CAAX ‐overexpressing cells, miR‐205 expression was also significantly increased by SCH 772984. Moreover, miR‐205 expression was significantly increased by treatment with DNA methyltransferase ( DNMT ) inhibitor 5‐aza‐2′‐deoxycytidine and expression of several DNMT family members was increased in both ErbB2‐ and Raf CAAX ‐overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR‐205 promoters were predominantly hypermethylated in both ErbB2‐ and Raf CAAX ‐overexpressing cells. Reporter activity of the putative miR‐205 promoters was reduced in both ErbB2‐overexpressing and Raf CAAX ‐overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR‐205 transcription via the Ras/Raf/ MEK / ERK pathway.