Promotion of microRNA-146a by histone deacetylase 4 silencing contributes to radiosensitization of esophageal carcinoma.

BACKGROUND

Histone deacetylases (HDACs) have been identified to be implicated in the carcinogenesis and cancer progression. The present study was performed to probe into the effect of HDAC4 on radioresistance of esophageal carcinoma (EC).

METHODS

The expression of HDAC4 in responders and non-responders to radiotherapy was characterized by RT-qPCR, immunohistochemistry, and Western blot analysis. EC cells were exposed to continuous fractionated X-ray irradiation, and their proliferation and apoptosis were evaluated by means of colony formation assay and flow cytometry based Annexin V-FITC/PI apoptosis assay in response to HDAC4 overexpression or silencing. Mechanistic investigation was conducted by means of in silico analysis and dual-luciferase reporter gene assay. Tumor xenografts derived from radioresistant EC cells were exposed to local X-ray irradiation in vivo for validation.

RESULTS

High expression of HDAC4 was detected in either tumor tissues derived from radiotherapy responders or radioresistant EC cells. Loss of HDAC4 contributed to suppressed proliferation and enhanced apoptosis of radioresistant EC cells. Moreover, our findings revealed that HDAC4 conferred radioresistance of EC by downregulating microRNA-146a (miR-146a). Interleukin-1 receptor-associated kinase 1 (IRAK1) was a target of miR-146a, and its knockdown promoted radiosensitivity. Silencing of HDAC4 radiosensitized EC cells both in vitro and in vivo via the miR-146a/IRAK1 axis.

CONCLUSION

Hence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.