Downregulation of METTL6 mitigates cell progression, migration, invasion and adhesion in hepatocellular carcinoma by inhibiting cell adhesion molecules

Abstract

RNA modifications have attracted increasing interest in recent years because they have been frequently implicated in various human diseases, including cancer, highlighting the importance of dynamic post-transcriptional modifications. Methyltransferase-like 6 (METTL6) is a member of the RNA methyltransferase family that has been identified in many cancers; however, little is known about its specific role or mechanism of action. In the present study, we aimed to study the expression levels and functional role of METTL6 in hepatocellular carcinoma (HCC), and further investigate the relevant pathways. To this end, we systematically conducted bioinformatics analysis of METTL6 in HCC using gene expression data and clinical information from a publicly available dataset. The mRNA expression levels of METTL6 were significantly upregulated in HCC tumor tissues compared to that in adjacent non-tumor tissues and strongly associated with poorer survival outcomes in patients with HCC. CRISPR/Cas9-mediated knockout of METTL6 in HCC cell lines remarkably inhibited colony formation, cell proliferation, cell migration, cell invasion and cell attachment ability. RNA sequencing analysis demonstrated that knockout of METTL6 significantly suppressed the expression of cell adhesion-related genes. However, chromatin immunoprecipitation sequencing results revealed no significant differences in enhancer activities between cells, which suggests that METTL6 may regulate genes of interest post-transcriptionally. In addition, it was demonstrated for the first time that METTL6 was localized in the cytosol as detected by immunofluorescence analysis, which indicates the plausible location of RNA modification mediated by METTL6. Our findings provide further insight into the function of RNA modifications in cancer and suggest a possible role of METTL6 as a therapeutic target in HCC.

The role of RNA modification in hepatocellular carcinoma

“…RNA modifications play a key role in regulating cell fate, an important regulator of HCC, in tumorigenesis and disease progression (Han et al, 2018;Pea et al, 2021;Braghini et al, 2022). The m6A, m7G, m5C, m1A, m3C, and ψ RNA modifications dynamically regulate the development of HCC, providing new strategies and possibilities for selecting possible therapeutic targets and investigating precisely directed intervention strategies for future HCC therapy (Tian et al, 2019;Bolatkan et al, 2022;Liu et al, 2022;Ren et al, 2022;Tong et al, 2022;Yu et al, 2022). As the most intensively studied RNA modification, m6A, and its regulators regulate the proliferation, migration, invasion, and EMT processes of HCC cells and are promising targets for HCC therapy (Zhou et al, 2019b;Liu et al, 2020a;Wang et al, 2020b;Zhang et al, 2020c;Qu et al, 2020;Wu et al, 2020;Zhu et al, 2020;Li et al, 2021e;Wei, 2021;Gu et al, 2022;Ren et al, 2022).…”

“…Bioinformatic analysis of METTL6 in HCC revealed that METTL6 mRNA expression levels were significantly upregulated in HCC and were closely associated with poorer patient survival outcomes. In contrast, METTL6 downregulation inhibited HCC progression by suppressing cell adhesion molecules and could be a potential therapeutic target for HCC (Bolatkan et al, 2022). METTL6mediated m3C tRNA methylation regulates gene expression, cellular homeostasis, translation, and tumor cell growth (Ignatova et al, 2020;Bolatkan et al, 2022).…”

“…In contrast, METTL6 downregulation inhibited HCC progression by suppressing cell adhesion molecules and could be a potential therapeutic target for HCC (Bolatkan et al, 2022). METTL6mediated m3C tRNA methylation regulates gene expression, cellular homeostasis, translation, and tumor cell growth (Ignatova et al, 2020;Bolatkan et al, 2022). Downregulation of METTL6 attenuates cell proliferation, invasion, and adhesion in HCC by inhibiting cell adhesion molecules and suppresses the malignant phenotype of HCC (Bolatkan et al, 2022).…”

“…METTL6mediated m3C tRNA methylation regulates gene expression, cellular homeostasis, translation, and tumor cell growth (Ignatova et al, 2020;Bolatkan et al, 2022). Downregulation of METTL6 attenuates cell proliferation, invasion, and adhesion in HCC by inhibiting cell adhesion molecules and suppresses the malignant phenotype of HCC (Bolatkan et al, 2022). METTL6 deficiency decreases the metabolic level of hepatic cells, inhibits HCC proliferation, and is significantly associated with a low survival rate in patients with HCC (Ignatova et al, 2020).…”

Correlation Between the RNA Methylation Genes and Immune Infiltration and Prognosis of Patients with Hepatocellular Carcinoma: A Pan-Cancer Analysis

“…Although several studies have assessed RNA methylation modifications in recent years, their mechanism of development in tumors is still not fully elucidated. 7 The Cancer Genome Atlas (TCGA) is a tumor genomics program that aims to use high-throughput genomic analysis techniques to better understand tumor characteristics and improve tumor prevention, diagnosis, and treatment. 8 , 9 Currently, TCGA contains information about sequencing results, transcriptome analysis, copy number variants, DNA methylation, and single nucleotide variants and covers 33 tumor types, thereby providing an advantage in pan-cancer research.…”