Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells.
Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103 (MGCD) exhibits effective anti-tumor activity by blocking proliferation and inducing cell death in malignant cells. However, the molecular mechanisms of HDACs inhibition induces cell death have not been well elucidated. In this study, we showed that MGCD effectively restored histone acetylation, suppressed cell growth and induced apoptosis in two-dimensional (2D) and three-dimensional (3D) cultured CNE1 and CNE2 nasopharyngeal carcinoma (NPC) cells. Importantly, MGCD arrested cell cycle at mitosis (M) phase with formation of multipolar spindles, which was associated with activated p53-mediated postmitotic checkpoint pathway to induce apoptotic cell death. Moreover, MGCD-induced apoptosis was decreased by inhibition of p53 using short interfering RNA (siRNA), suggesting that p53 was required for MGCD-induced cell apoptosis. Consistently, MGCD in combination with Nutlin-3, a MDM2 inhibitor showed synergistic effect on inducing apoptosis in 2D and 3D cultured CNE2 cells. Collectively, our data revealed that MGCD induced p53-dependent cell apoptosis following formation of multipolar spindles in NPC cells, suggesting the therapeutic potential of combinations of HDACs and MDM2 inhibitors for NPC treatment.
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.|Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Min
M
Yan
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.
Yuan-Min
YM
Qian
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.|Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Cai-Feng
CF
Yue
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.
Zi-Feng
ZF
Wang
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.
Bi-Cheng
BC
Wang
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.
Wei
W
Zhang
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.|Department of Medical Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Fei-Meng
FM
Zheng
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China.
Quentin
Q
Liu
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D018929:Cell Culture Techniques / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C523184:mocetinostat; D006655:Histone Deacetylases
Nutlin-3; apoptosis; histone deacetylases; p53; spindle