KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a

Abstract

Background 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.

Systemic Profiling of KDM5 Subfamily Signature in Non-Small-Cell Lung Cancer

“…32 It has been revealed that KDM5C mediate miR-133a expression to suppress development and metastases of lung cancer by targeting PTBP1. 33 Across these databases, we consistently observed elevated expression levels of KDM5B/C and relatively high gene mutations in either LUAD or LUSC, which remind us of their oncogenic properties under cancer type-specific context.…”

Lysine demethylase 5C epigenetically reduces transcription of ITIH1 that results in augmented progression of liver hepatocellular carcinoma

“…Several key methyltransferases and demethylases, such as SETDB1, EZH2, ASH1L, WHSC1, NSD1, EHMT2, KDM1A, KDM3A, KDM3B, KDM4B, and KDM5B, have been demonstrated to be frequently upregulated in HCC tumor tissues and possibly implicated in its pathogenesis 20–22 . KDM5C has been suggested as a pan‐cancer‐driver 11 and reportedly involved in the tumorigenesis of cancers of the colon, 12 stomach, 23 and lung 24 . Importantly, KDM5C has also been reported to augment migration, invasion and epithelial–mesenchymal transition of HCC cells 13 .…”

“…[20][21][22] KDM5C has been suggested as a pan-cancer-driver 11 and reportedly involved in the tumorigenesis of cancers of the colon, 12 stomach, 23 and lung. 24 Importantly, KDM5C has also been reported to augment migration, invasion and epithelial-mesenchymal transition of HCC cells. 13 In the present study, data from publicly accessible databases suggested that KDM5C was highly expressed in LIHC and indicated poor patient prognosis, and high-expression profiling of KDM5C was confirmed in LIHC cell lines.…”

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

“…It promotes breast cancer tumorigenesis by activating ERα-target genes or repressing BRMS1 expression and protects breast cancer cells from immune surveillance by repressing type I interferons and interferon-stimulated genes [36,142]. KDM5C also plays oncogenic roles in gastric cancer, colon cancer, hepatocellular carcinoma, and lung cancer by suppressing p53, FBXW7, BMP7, and miR-133a, respectively [143][144][145][146].…”