title: Regulation of the Mechanism of TWIST1 Transcription by BHLHE40 and BHLHE41 in Cancer Cells.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan asanoma@med.kyushu-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Asanoma
authors.affiliation: Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ge
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Yamane
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Miyanari
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University, Kyoto, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Takao
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ohgami
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Akimasa
authors.initials: A
authors.lastname: Ichinoe
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Sonoda
authors.affiliation: Research Center for Environment and Developmental Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Wake
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D016329:Sp1 Transcription Factor / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C107989:BHLHE40 protein, human; C422085:BHLHE41 protein, human; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C108209:SP1 protein, human; C103173:TWIST1 protein, human