Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel
Tianyang Yun1,*, Yang Liu1,*, Dan Gao2,5, Enqiang Linghu2, Malcolm V. Brock3, Dongtao Yin1, Qimin Zhan4, James G. Herman3 and Mingzhou Guo2
1 Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing, China
2 Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, China
3 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, U.S.A
4 State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
5 Medical College of NanKai University, Tianjin, China
* These authors contributed to this work equally
Correspondence:
Mingzhou Guo, email:
Correspondence:
James G. Herman, email:
Keywords: DNA methylation, CHFR, esophageal squamous cell cancer, docetaxel, paclitaxel, chemo-sensitivity, 5-aza-2’-deoxycytidine
Received: September 17, 2014 Accepted: December 30, 2014 Published: December 31, 2014
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution.
