Silencing lncRNA‐DARS‐AS1 suppresses nonsmall cell lung cancer progression by stimulating miR‐302a‐3p to inhibit ACAT1 expression

Abstract

Long noncoding RNAs (LncRNAs) have been gaining attention as potential therapeutic targets for lung cancer. In this study, we investigated the expression and biological behavior of lncRNA DARS‐AS1, its predicted interacting partner miR‐302a‐3p, and ACAT1 in nonsmall cell lung cancer (NSCLC). The transcript level of DARS‐AS1, miR‐302a‐3p, and ACAT1 was analyzed using qRT‐PCR. Endogenous expression of ACAT1 and the expression of—and changes in—AKT/ERK pathway‐related proteins were determined using western blotting. MTS, Transwell, and apoptosis experiments were used to investigate the behavior of cells. The subcellular localization of DARS‐AS1 was verified using FISH, and its binding site was verified using dual‐luciferase reporter experiments. The binding of DARS‐AS1 to miR‐302a‐3p was verified using RNA co‐immunoprecipitation. In vivo experiments were performed using a xenograft model to determine the effect of DARS‐AS1 knockout on ACAT1 and NSCLC. lncRNA DARS‐AS1 was upregulated in NSCLC cell lines and tissues and the expression of lncRNA DARS‐AS1 was negatively correlated with survival of patients with NSCLC. Knockdown of DARS‐AS1 inhibited the malignant behaviors of NSCLC via upregulating miR‐302a‐3p. miR‐302a‐3p induced suppression of malignancy through regulating oncogene ACAT1. This study demonstrates that the DARS‐AS1‐miR‐302a‐3p‐ACAT1 pathway plays a key role in NSCLC.

Targeting ACAT1 in cancer: from threat to treatment

“…ACAT1 predominantly signals through inhibition of PDC by PDP1 and PDHA acetylation to enhance glycolysis and tumor growth, indicating the ACAT1-PDP1-PDHA axis a promising anti-cancer target ( 46 ). lncRNA DARS-AS1 inhibition attenuated non-small cell lung cancer development by activating miR-302a-3p to inhibit ACAT1 expression ( 47 ). It has been demonstrated that Kras-specific antigenic peptides in combination of avasimibe could promote CD8+ T cell infiltration and impair lung tumor progression ( 48 ).…”