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 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.

Overexpression of the Circadian Clock Gene Bmal1 Increases Sensitivity to Oxaliplatin in Colorectal Cancer

“…Our findings are consistent with those of multiple studies demonstrating the role of Bmal1 in the suppression of cell proliferation, indicating that Bmal1 is a potential tumor suppressor gene (13)(14)(15). In contrast to our findings, another recent study (46) reported that Bmal1 promotes proliferation in malignant pleural mesothelioma. On the basis of this difference, we suspect that Bmal1 might play different roles in different tumor types, which further highlights the complicated mechanisms involved in tumorigenesis.…”

A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells

“…Because KS15 can enhance the actions of CLOCK:BMAL1, it is likely that the reduction in the Bmal1 level does not interfere with the anti-tumor activity of KS15. On the other hand, a recent study showed that repression of BMAL1 induces apoptosis and cell-cycle disruption in mesothelioma cells [41], suggesting the possibility of a novel contribution of Bmal1 reduction to the anti-tumor activity of KS15.…”

Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma

“…The median survival of 1 yr after diagnosis and the poor quality of life involved have prompted researchers to identify effective therapies with variable clinical results so far (48,73). MPM poses a diagnostic challenge, since its detection in early stages is often proven to be problematic, thus urging the importance of biomarker development (15,71).…”