N6-methyladenosine-regulated ADIRF impairs lung adenocarcinoma metastasis and serves as a potential prognostic biomarker

Abstract

Aberrant expression of adipogenic regulatory factors (ADIRF) in tumor cells is critical for tumor growth and metastasis. N6-methyladenosine (m6A) modifications have an important role in a variety of biological activities. Our study aimed to investigate the role of ADIRF in adenocarcinoma and to elucidate the regulatory role of m6A signaling on ADIRF. Differential expression of genes in tumor and normal tissues was analyzed using the LUAD dataset (GSE1987). The Kaplan-Meier method and receiver operating characteristic (ROC) curve analysis were performed to evaluate the prognostic and diagnostic value of ADIRF in LUAD. Loss-of-function or gain-of-function experiments were performed to study the effect of ADIRF on LUAD growth in vitro. The molecular mechanism of action of ADIRF in LUAD was confirmed using a dual-luciferase reporter system and MeRIP-qPCR. We identified a loss of ADIRF expression in LUAD tissues and cells. Furthermore, the restoration of ADIRF levels attenuated LUAD cell growth and metastasis in vitro. Mechanistically, an m6A “eraser,” α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), eliminated the ADIRF m6A modification motif and further blocked the binding of the YTH domain-containing 2 (YTHDC2)-binding protein to ADIRF. At the molecular level, ALKBH5 enrichment increased ADIRF mRNA levels and prevented the attenuation of ADIRF mRNA by YTHDC2. The effects of ALKBH5 overexpression could also extend to the inhibition of LUAD cell proliferation and metastasis. This study linked ADIRF with the m6A modifying regulators ALKBH5 and YTHDC2, providing a promising molecular intervention for LUAD and deepening the understanding of LUAD mechanisms.