title: The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the mesothelial cells lining the parietal pleura and it exhibits poor prognosis. Although there has been significant progress in MPM treatment, development of more efficient therapeutic approaches is needed. BMAL1 is a core component of the circadian clock machinery and its constitutive overexpression in MPM has been reported. Here, we demonstrate that BMAL1 may serve as a molecular target for MPM. The majority of MPM cell lines and a subset of MPM clinical specimens expressed higher levels of BMAL1 compared to a nontumorigenic mesothelial cell line (MeT-5A) and normal parietal pleural specimens, respectively. A serum shock induced a rhythmical BMAL1 expression change in MeT-5A but not in ACC-MESO-1, suggesting that the circadian rhythm pathway is deregulated in MPM cells. BMAL1 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in two MPM cell lines (ACC-MESO-1 and H290) but not in MeT-5A. Notably, BMAL1 depletion resulted in cell cycle disruption with a substantial increase in apoptotic and polyploidy cell population in association with downregulation of Wee1, cyclin B and p21(WAF1/CIP1)  and upregulation of cyclin E expression. BMAL1 knockdown induced mitotic catastrophe as denoted by disruption of cell cycle regulators and induction of drastic morphological changes including micronucleation and multiple nuclei in ACC-MESO-1 cells that expressed the highest level of BMAL1. Taken together, these findings indicate that BMAL1 has a critical role in MPM and could serve as an attractive therapeutic target for MPM.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan.
authors.forename: Momen
authors.initials: M
authors.lastname: Elshazley
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Hase
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamashita
authors.forename: Kenya
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Futoshi
authors.initials: F
authors.lastname: Ishiguro
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoi
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Usami
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Masashi
authors.initials: M
authors.lastname: Kondo
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002940:Circadian Rhythm / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D034741:RNA, Small Interfering