Targeting EZH2 regulates tumor growth and apoptosis through modulating mitochondria dependent cell-death pathway in HNSCC
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Xuan Zhou1,*, Yu Ren2,*, Lingping Kong1,*, Guoshuai Cai3,*, Shanshan Sun1, Wangzhao Song3,4, Yu Wang1, Rui Jin1, Lisha Qi3,4, Mei Mei2, Xudong Wang1, Chunsheng Kang5, Min Li1,6 and Lun Zhang1
1 Department of Maxillofacial and Otorhinolaryngology Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China
2 Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China
3 Department of Genetics, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
4 Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
5 Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, China
6 Department of Surgery, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
* These authors have contributed equally to this work
Lun Zhang, email:
Min Li, email:
Chunsheng Kang, email:
Keywords: EZH2 (enhancer of zeste homolog 2), MICU-1 (mitochondrial calcium uptake 1), H3K27me3, apoptosis, head and neck squamous cell carcinoma (HNSCC)
Received: June 29, 2015 Accepted: August 27, 2015 Published: September 10, 2015
EZH2 is a negative prognostic factor and is overexpressed or activated in most human cancers including head and neck squamous cell carcinoma (HNSCC). Analysis of The Cancer Genome Atlas (TCGA) HNSCC data indicated that EZH2 over-expression was associated with high tumor grade and conferred poor prognosis. EZH2 inhibition triggered cell apoptosis, cell cycle arrest and decreased cell growth in vitro. MICU1 (mitochondrial calcium uptake1) was shown to be down regulated when EZH2 expression was inhibited in HNSCC. When the EZH2 and MICU1 were inhibited, HNSCC cells became susceptible to cell cycle arrest and apoptosis. Mitochondrial membrane potential and cytosolic Ca2+ concentration analysis suggested that EZH2 and MICU1 were required to maintain mitochondrial membrane potential stability. A xenograft tumor model was used to confirm that EZH2 depletion inhibited HNSCC cell growth and induced tumor cell apoptosis. In summary, EZH2 is a potential anti-tumor target in HNSCC.
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