m⁶A‐Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis

Abstract

The importance of mRNA N6‐methyladenosine (m6A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m6A modification is interesting but remains uncharacterized. Here, this work shows that m6A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial‐mesenchymal‐transition (EMT) and confers LUAD cells plasticity to metastasize through m6A‐dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m6A‐modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1‐mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m6A‐dependent IGF2BP3‐mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m6A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.

IGF2BP3 promotes glutamine metabolism of endometriosis by interacting with UCA1 to enhances the mRNA stability of GLS1

“…Further investigation demonstrated that UCA1 and IGF2BP3 together enhanced the stability of GLS1 mRNA. Additionally, IGF2BP3 played a crucial role in regulating post-transcriptional gene expression (Tang et al 2023 ; Yang et al 2023a , b ). Starbase revealed that there was a direct binding interaction between IGF2BP3 and the 3'-UTR region of the GLS1 gene.…”

“…These IGF2BPs modulate key regulatory factors involved in cell division and metabolism, exerting a significant impact on disease progression (Degrauwe et al 2016 ; Elcheva et al 2023 ). Insulin like growth factor II mRNA binding protein 3 (IGF2BP3), also recognized as IMP3, KOC and VICKZ3, serves as a tumorigenic protein implicated in various cancers (Wan et al 2022 ; Yang et al 2023a , b ; Yu et al 2022 ). Yang et al suggested that IGF2BP3 held prognostic value as a marker for ovarian clear cell carcinoma (CCC) (Bi et al 2016 ).…”

Systematic analysis of IGF2BP family members in non-small-cell lung cancer

“…IGF2BP3 overexpression stabilizes anti-ferroptotic factors like SLC3A2 and ACSL3, inhibiting ferroptosis in lung adenocarcinoma cells [ 52 ]. Furthermore, IGF2BP3 contributes to lung adenocarcinoma progression by modulating the PI3K/AKT signaling pathway [ 53 ] and promoting partial EMT and metastasis through the MCM5/Notch axis [ 54 ]. Targeting IGF2BPs has been suggested in several studies as a strategy to inhibit malignant behaviors of cancers in vitro [ 55 – 58 ].…”

Regulatory mechanisms and therapeutic implications of insulin-like growth factor 2 mRNA-binding proteins, the emerging crucial m6A regulators of tumors

“…Furthermore, IGF2BP2 increases the stability of SLUG mRNA which is an EMT-related transcriptional factor via binding to its m 6 A site in the CDS, leading to lymphatic metastasis in head and neck squamous carcinoma (HNSCC) [46]. Additionally, IGF2BP3mediated m 6 A modification stabilizes minichromosome maintenance complex component (MCM5) mRNAs and activates the Notch signaling, leading to EMT and metastasis in lung adenocarcinoma [47]. Altogether, these studies demonstrate that IGF2BPs facilitate tumor angiogenesis and EMT, which are crucial for tumor metastasis.…”