RNA Editing Enzyme ADAR1 Regulates METTL3 in an Editing Dependent Manner to Promote Breast Cancer Progression via METTL3/ARHGAP5/YTHDF1 Axis

Abstract

A-to-I RNA editing and m6A modification are two of the most prevalent types of RNA modifications controlling gene expression in mammals and play very important roles in tumorigenesis and tumor progression. However, the functional roles and correlations of these two RNA modifications remain to be further investigated in cancer. Herein, we show that ADAR1, an A-to-I RNA-editing enzyme, interacts with METTL3 and increases its protein level to promote the proliferation, migration and invasion of breast cancer cells through a mechanism connecting ADAR1, METTL3 and YTHDF1. We show that both ADAR1 and METTL3 are upregulated in breast cancer samples, and ADAR1 positively correlates with METTL3; ADAR1 edits METTL3 mRNA and changes its binding site to miR532-5p, leading to increased METTL3 protein, which further targets ARHGAP5, recognized by YTHDF1. Additionally, we show that loss of ADAR1 significantly inhibits breast cancer growth in vivo. Collectively, our findings identify the ADAR1–METTL3 axis as a novel, important pathway that connects A-to-I editing and m6A RNA modifications during breast cancer progression.

YTHDF1 enhances stemness and chemoresistance in triple‐negative breast cancer cells by upregulating SIAH2

“…m6A RNA methylation is a key biological process in tumor progression and drug resistance. The m6A RNA methylation reader YTHDF1 plays oncogenic roles in a variety of tumors and is involved in tumor drug resistance 25,26 . In breast cancer, YTHDF1 can promote glycolytic metabolism to drive breast cancer by binding to PKM2, 22 it can also promote breast cancer progression by promoting FOXM1 translation 27 .…”

“…The m6A RNA methylation reader YTHDF1 plays oncogenic roles in a variety of tumors and is involved in tumor drug resistance. 25,26 In breast cancer, YTHDF1 can promote glycolytic metabolism to drive breast cancer by binding to PKM2, 22 it can also promote breast cancer progression by promoting FOXM1 translation. 27 In the hypoxic microenvironment, YTHDF1 can be induced to up-regulate and promote the proliferation and metastasis of breast cancer cells.…”

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…Adenosine deaminase acting on RNA 1 (ADAR1) and METTL3 were upregulated in breast cancer samples [ 91 ]. The loss of ADAR1 significantly inhibited breast cancer growth in vivo [ 91 ].…”

“…Adenosine deaminase acting on RNA 1 (ADAR1) and METTL3 were upregulated in breast cancer samples [ 91 ]. The loss of ADAR1 significantly inhibited breast cancer growth in vivo [ 91 ]. ADAR1 was shown to edit METTL3 mRNA and increases METTL3 protein, which further targeted Rho GTPase-activating protein 5 (ARHGAP5) in a YTHDF1-dependent manner [ 91 ].…”

“…LINC also decreased the expression of PTEN in chronic myelocytic leukemia cells [ 93 ]. The relative expression of LC3II, Beclin-1, ATG7, and ATG5 was decreased in cells treated with LINC00470, and down-regulated PTEN expression was observed in chemo-resistant cells [ 91 ]. Moreover, the downregulation of METTL3 also restored the normal levels of PTEN m6 A modification and LINC00470 expression in chemo-resistant cells [ 93 ].…”