OncoTargets and Therapy (Feb 2021)
KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a
Abstract
Quan Zhang,* Lei Xu,* Jianjun Wang, Xiaoming Zhu, Zeheng Ma, Junfeng Yang, Jiwei Li, Xiangbo Jia, Li Wei Department of Thoracic Surgery, Zhengzhou Key Laboratory of Surgical Treatment for End-Stage Lung Diseases, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li WeiDepartment of Thoracic Surgery, Zhengzhou Key Laboratory of Surgical Treatment for End-Stage Lung Diseases, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan, People’s Republic of ChinaTel/Fax +86-18339223972Email [email protected]: KDM5C, a histone H3K4-specific demethylase, possess various biological functions in development of cancers. However, its relation to the microRNA (miRNA) regulation in lung cancer remains unknown. This study aims to study the regulatory role of KDM5C on modification of miR-133a in the progression of lung cancer.Methods: Differentially expressed miRNAs were filtered from 34 paired lung cancer and paracancerous tissues. The correlation between miR-133a expression and the prognosis of lung cancer patients was determined by a bioinformatics website. Furthermore, malignant aggressiveness of lung cancer cells was detected after miR-133a upregulation by CCK-8, flow cytometry, and Transwell assays and in vivo tumorigenesis and metastasis experiments. Subsequently, we analyzed mRNA downregulated in cells overexpressing miR-133a using m microarray analysis and expounded the upstream regulatory mechanism of miR-133a using bioinformatics website prediction and functional validation.Results: miR-133a was reduced in lung cancer tissues, and patients with low expression of miR-133a have worse survival rates. miR-133a restoration curtailed growth and metastasis of lung cancer cells in vitro and in vivo. Moreover, miR-133a downregulated PTBP1 expression, whereas overexpression of PTBP1 attenuated the suppressive effect of miR-133a on lung cancer cell aggressiveness. The level of methylation modification of miR-133a was reduced in lung cancer cells. KDM5C inhibited the expression of miR-133a by promoting the demethylation modification of its promoter histone.Conclusion: Histone demethylase KDM5C inhibits the expression of miR-133a by elevating the demethylation modification of the promoter histone of miR-133a, thereby promoting the expression of PTBP1, which finally accelerates lung cancer cell growth and metastasis.Keywords: KDM5C, microRNA-133a, lung cancer, PTBP1, histone methylation modification
