Circadian clock components RORα and Bmal1 mediate the anti-proliferative effect of MLN4924 in osteosarcoma cells.
The anticancer small molecule MLN4924, a Nedd8-activating enzyme (NAE) inhibitor, triggers cell-cycle arrest, apoptosis, and senescence in cancer cells. In this study, we demonstrate that MLN4924 suppresses osteosarcoma cell proliferation by inducing G2/M cell cycle arrest and apoptosis. Our results indicate that MLN4924 stabilizes the retinoid orphan nuclear receptor alpha (RORα) by decreasing its ubiquitination. RNA interference of RORα attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. MLN4924 up-regulates the expression of p21 and Bmal1, two transcriptional targets of RORα. However, p21 plays a minimal role in the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells. In contrast, Bmal1 suppression by siRNA attenuates the anti-proliferative effect of MLN4924 in U2OS osteosarcoma cells, indicating that the MLN4924-mediated cell growth inhibition is mediated by Bmal1. These results show MLN4924 to be a promising therapeutic agent for the treatment of osteosarcoma and suggest that MLN4924-induced tumor growth inhibition is mediated by the circadian clock components RORα and Bmal1.
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Shuju
S
Zhang
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Jiaming
J
Zhang
Xiangya Stomatological Hospital, Central South University, Changsha, Hunan 410078, China.
Zhiyuan
Z
Deng
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Huadie
H
Liu
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Wei
W
Mao
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Fang
F
Jiang
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Zanxian
Z
Xia
The State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
Jia-Da
JD
Li
D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D057906:Circadian Clocks; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D014408:Biomarkers, Tumor; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011743:Pyrimidines; C539933:pevonedistat
Bmal1; MLN4924; RORα; neddylation; osteosarcoma