J Cancer 2016; 7(9):1152-1162. doi:10.7150/jca.14745
Downregulation of Ubiquitin-conjugating Enzyme UBE2D3 Promotes Telomere Maintenance and Radioresistance of Eca-109 Human Esophageal Carcinoma Cells
1. Hubei Key Laboratory of Tumor Biological Behavior, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China;
2. Department of Radiation Oncology & Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China;
3. Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
* These authors contributed equally to this work.
Yang H, Wu L, Ke S, Wang W, Yang L, Gao X, Fang H, Yu H, Zhong Y, Xie C, Zhou F, Zhou Y. Downregulation of Ubiquitin-conjugating Enzyme UBE2D3 Promotes Telomere Maintenance and Radioresistance of Eca-109 Human Esophageal Carcinoma Cells. J Cancer 2016; 7(9):1152-1162. doi:10.7150/jca.14745. Available from http://www.jcancer.org/v07p1152.htm
Ubiquitin-conjugating enzyme UBE2D3 is an important member of the ubiquitin-proteasome pathways. Our previous study showed that the expression of UBE2D3 was negatively related to human telomerase reverse transcriptase (hTERT) and radioresistance in human breast cancer cells. However, in esophageal carcinoma, the exact effects and mechanisms of UBE2D3 in radioresistance remain unclear. This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins. UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio. Furthermore, UBE2D3 downregulation was associated with increased G1-S phase transition and prolonged IR-induced G2/M arrest through over expression of cyclin D1, decrease of CDC25A expression and promotion of the ATM/ATR-Chk1-CDC25C pathway. Moreover, UBE2D3 downregulation reduced spontaneous DNA double-strand breaks and accelerated the repair of DNA damage induced by IR. The current data thus demonstrate that UBE2D3 downregulation enhances radioresistance by increased telomere homeostasis and prolonged IR-induced G2/M arrest, but decreases the IR-induced apoptosis and the number of DNA damage foci. These results suggest that UBE2D3 might be a potential molecular target to improve radiotherapy effects in esophageal carcinoma.
Keywords: UBE2D3, telomere maintenance, radioresistance, esophageal carcinoma, DNA damage repair.