title: miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer.
abstract: Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nishikawa
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tatematsu
authors.forename: Ayumu
authors.initials: A
authors.lastname: Taguchi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C065500:ASCL1 protein, human; C540933:MIRN375 microRNA, human; C088374:YAP1 protein, human