The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma

Momen Elshazley, Mitsuo Sato, Tetsunari Hase, Ryo Yamashita, Kenya Yoshida, Shinya Toyokuni, Futoshi Ishiguro, Hirotaka Osada, Yoshitaka Sekido, Kohei Yokoi, Noriyasu Usami, David S. Shames, Masashi Kondo, Adi F. Gazdar, John D. Minna, Yoshinori Hasegawa

Research output: Contribution to journalArticle

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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 p21WAF1/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.

Original languageEnglish
Pages (from-to)2820-2831
Number of pages12
JournalInternational Journal of Cancer
Volume131
Issue number12
DOIs
Publication statusPublished - 15-12-2012

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Circadian Clocks
Genes
Therapeutics
Mesothelial Neoplasms
Cell Line
Cell Cycle
Malignant Mesothelioma
Cyclin B
Cyclin E
Polyploidy
Pleura
Circadian Rhythm
Shock
Up-Regulation
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Elshazley, M., Sato, M., Hase, T., Yamashita, R., Yoshida, K., Toyokuni, S., ... Hasegawa, Y. (2012). The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. International Journal of Cancer, 131(12), 2820-2831. https://doi.org/10.1002/ijc.27598
Elshazley, Momen ; Sato, Mitsuo ; Hase, Tetsunari ; Yamashita, Ryo ; Yoshida, Kenya ; Toyokuni, Shinya ; Ishiguro, Futoshi ; Osada, Hirotaka ; Sekido, Yoshitaka ; Yokoi, Kohei ; Usami, Noriyasu ; Shames, David S. ; Kondo, Masashi ; Gazdar, Adi F. ; Minna, John D. ; Hasegawa, Yoshinori. / The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. In: International Journal of Cancer. 2012 ; Vol. 131, No. 12. pp. 2820-2831.
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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 p21WAF1/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.",
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Elshazley, M, Sato, M, Hase, T, Yamashita, R, Yoshida, K, Toyokuni, S, Ishiguro, F, Osada, H, Sekido, Y, Yokoi, K, Usami, N, Shames, DS, Kondo, M, Gazdar, AF, Minna, JD & Hasegawa, Y 2012, 'The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma', International Journal of Cancer, vol. 131, no. 12, pp. 2820-2831. https://doi.org/10.1002/ijc.27598

The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. / Elshazley, Momen; Sato, Mitsuo; Hase, Tetsunari; Yamashita, Ryo; Yoshida, Kenya; Toyokuni, Shinya; Ishiguro, Futoshi; Osada, Hirotaka; Sekido, Yoshitaka; Yokoi, Kohei; Usami, Noriyasu; Shames, David S.; Kondo, Masashi; Gazdar, Adi F.; Minna, John D.; Hasegawa, Yoshinori.

In: International Journal of Cancer, Vol. 131, No. 12, 15.12.2012, p. 2820-2831.

Research output: Contribution to journalArticle

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AU - Sato, Mitsuo

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AU - Yamashita, Ryo

AU - Yoshida, Kenya

AU - Toyokuni, Shinya

AU - Ishiguro, Futoshi

AU - Osada, Hirotaka

AU - Sekido, Yoshitaka

AU - Yokoi, Kohei

AU - Usami, Noriyasu

AU - Shames, David S.

AU - Kondo, Masashi

AU - Gazdar, Adi F.

AU - Minna, John D.

AU - Hasegawa, Yoshinori

PY - 2012/12/15

Y1 - 2012/12/15

N2 - 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 p21WAF1/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.

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Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S et al. The circadian clock gene BMAL1 is a novel therapeutic target for malignant pleural mesothelioma. International Journal of Cancer. 2012 Dec 15;131(12):2820-2831. https://doi.org/10.1002/ijc.27598