Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, 213000, China.
Department of Pathology, Changzhou Tumor Hospital, Soochow University, No. 68, Honghe Road, Xinbei District, Changzhou, 213000, Jiangsu, China.
J Transl Med. 2022 Feb 22;20(1):101. doi: 10.1186/s12967-021-03171-z.
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).
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.
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.
Hence, loss of HDAC4 upregulated miR-146a to limit radioresistance. This study aids in the better understanding about mechanism responsible for radioresistance of EC.
组蛋白去乙酰化酶（HDACs）已被确定与癌症的发生和发展有关。本研究旨在探讨 HDAC4 对食管癌（EC）放射抵抗的影响。
通过 RT-qPCR、免疫组织化学和 Western blot 分析，研究了放疗反应者和非反应者中 HDAC4 的表达。将 EC 细胞暴露于连续分割 X 射线照射下，通过集落形成实验和流式细胞术检测 HDAC4 过表达或沉默后细胞增殖和凋亡。通过计算机分析和双荧光素酶报告基因实验进行机制研究。通过体内局部 X 射线照射验证源自放射抵抗 EC 细胞的肿瘤异种移植物。
在放疗反应者的肿瘤组织或放射抵抗的 EC 细胞中均检测到 HDAC4 的高表达。HDAC4 的缺失导致放射抵抗的 EC 细胞增殖受到抑制，凋亡增强。此外，我们的研究结果表明，HDAC4 通过下调 microRNA-146a（miR-146a）赋予 EC 放射抵抗性。白细胞介素 1 受体相关激酶 1（IRAK1）是 miR-146a 的靶标，其敲低可促进放射敏感性。沉默 HDAC4 通过 miR-146a/IRAK1 轴在体外和体内均使 EC 细胞放射敏感。
因此，HDAC4 的缺失上调 miR-146a 以限制放射抵抗性。本研究有助于更好地理解 EC 放射抵抗的机制。
