Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization

Abstract

Background: N⁶-methyladenosine (m⁶A) has been identified to regulate the tumorigenesis and development of various tumors, including non-small cell lung cancer (NSCLC). Isoliquiritigenin (ISL), derived from the Chinese herb licorice, shows a significant anti-tumor activity on multiple human cancers. However, the role of ISL on NSCLC through m⁶A is still unclear.

Purpose: Here, we investigated the anti-tumor effect of ISL on NSCLC, and explored whether ISL affected the NSCLC phenotype by modulating its m⁶A modification.

Methods: Cell proliferation, migration and invasion assays were performed to evaluate the inhibitory effects of ISL on NSCLC cells. M⁶A enrichment was determined by m⁶A quantitative analysis. The mechanism regarding IGF2BP3 was explored using RIP-PCR, MeRIP-qPCR and RNA decay analysis.

Results: ISL significantly repressed the proliferation, migration and invasion of NSCLC cells in vitro. In addition, m⁶A reader IGF2BP3 expression significantly increased in NSCLC tissues compared to adjacent tissues, and was positively correlated with NSCLC patients' poor survival. Mechanistically, ISL reduced m⁶A modification and down-regulated IGF2BP3 expression in NSCLC. Furthermore, IGF2BP3 enhanced the mRNA stability of twist family bHLH transcription factor 1 (TWIST1) in m⁶A-dependent manner. Moreover, ISL treatment combined with TWSIT1 knockdown effectively reversed IGF2BP3 overexpression-induced NSCLC cells' proliferation, migration and invasion.

Conclusion: Our findings uncover that ISL might function as an anticarcinogen through targeting IGF2BP3/m⁶A/TWIST1 axis for NSCLC.

Keywords: IGF2BP3; Isoliquiritigenin; Non-small cell lung cancer; TWIST1; m(6)A.