Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells

Author:

Asanoma Kazuo1,Liu Ge2,Yamane Takako1,Miyanari Yoko1,Takao Tomoka3,Yagi Hiroshi1,Ohgami Tatsuhiro1,Ichinoe Akimasa1,Sonoda Kenzo1,Wake Norio2,Kato Kiyoko1

Affiliation:

1. Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

2. Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan

3. Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University, Kyoto, Japan

Abstract

ABSTRACT BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Our in vitro assays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectors SNAI1 , SNAI2 , and TWIST1 . We identified the critical promoter regions of TWIST1 for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity of TWIST1 and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectors in vitro . Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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