Overcoming of Radioresistance in Non-small Cell Lung Cancer by microRNA-320a Through HIF1α-Suppression Mediated Methylation of PTEN

Abstract

Background Radioresistance is a major challenge in the use of radiotherapy for the treatment of lung cancer while microRNAs (miRs) have been reported to participate in multiple essential cellular processes including radiosensitization. This study was conducted with the main objective of investigating the potential role of miR-320a in radioresistance of non-small cell lung cancer (NSCLC) via the possible mechanism related to HIF1α, KDM5B, and PTEN. Methods Firstly, NSCLC radiosensitivity-related microarray dataset GSE112374 was obtained. Then, the expression of miR-320a, HIF1α, KDM5B, and PTEN was detected in the collected clinical NSCLC samples, followed by Pearson’s correlation analysis. Subsequently, ChIP assay was conducted to determine the content of the PTEN promoter fragment enriched by the IgG antibody and H3K4me3 antibody. Finally, a series of in vitro and in vivo assays were performed in order to evaluate the effects of miR-320a on radioresistance of NSCLC with the involvement of HIF1α, KDM5B, and PTEN. Results The microarray dataset GSE112374 presented with a high expression of miR-320a in NSCLC radiosensitivity samples, which was further confirmed in our clinical samples with the use of reverse transcription-quantitative polymerase chain reaction. Moreover, miR-320a negatively targeted HIF1α, inhibiting radioresistance of NSCLC. Interestingly, miR-320a suppressed the expression of KDM5B, and KDM5B was found to enhance the radioresistance of NSCLC through the downregulation of PTEN expression. The inhibition of miR-320a in radioresistance of NSCLC was also reproduced by in vivo assay. Conclusion Taken together, our findings were suggestive of the inhibitory effect of miR-320a on radioresistance of NSCLC through HIF1α-suppression mediated methylation of PTEN.

Transmembrane Protein-Based Risk Model and H3K4me3 Modification Characteristics in Lung Adenocarcinoma

“…However, H3K4me3 demethylation caused by the loss of KMT2D function in the germinal center of lymphoma led to rapid tumor progression, and the re-establishing of H3K4 trimethylation caused significant tumor growth inhibition ( 49 ). It was also reported that KDM5B downregulated PTEN expression by suppressing the accumulation of H3K4me3 in the PTEN promoter region so as to enhance the radioresistance of NSCLC ( 50 ). Therefore, the current molecular biology experiments have shown the complex and contradictory functional characteristics of H3K4me3 in tumors.…”

Overcoming radio-resistance in esophageal squamous cell carcinoma via hypermethylation of PIK3C3 promoter region mediated by KDM5B loss

“…Interestingly, KDM5B was found to promote the radio-resistance of non-small cell lung cancer through the decline of PTEN expression [ 26 ]. As a consequence, we postulated that KDM5B exerts a similar effect on ESCC cells via regulating the expression of PIK3C3.…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…KDM5B also induces a cancer stem cell-like phenotype by activating the c-MET signaling pathway in NSCLC cells [110]. Furthermore, KDM5B confers radioresistance to NSCLC cells [111,112]. Bayo et al showed that at sites of DNA damage, H3K4me3 interferes with the recruitment of DNA repair factors, and that in irradiated cancer cells, KDM5B facilitates DNA repair by removing H3K4me3 at those sites [111].…”