USP10-stabilized IGF2BP3 promotes tumor growth via m⁶A-modified SKP2 mRNA in non-small-cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Non-small-cell lung cancer (NSCLC) presents a significant global health challenge.
• Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is implicated as an oncogenic N6-methyladenosine "reader" in various solid tumors.
• The specific role and underlying mechanisms of IGF2BP3 in NSCLC remain largely unelucidated.

Purpose of the Study:

• To investigate the prognostic significance and functional role of IGF2BP3 in NSCLC.
• To elucidate the molecular mechanisms by which IGF2BP3 influences NSCLC progression.
• To identify regulatory factors controlling IGF2BP3 stability in NSCLC.

Main Methods:

• Analysis of IGF2BP3 expression in NSCLC patient cohorts to correlate with prognosis.
• In vitro and in vivo experiments to assess the impact of IGF2BP3 deficiency on NSCLC cell proliferation and tumor growth.
• Mechanistic studies involving mRNA stability assays and protein-protein interaction analyses.
• Screening of deubiquitinase (DUB) enzymes to identify regulators of IGF2BP3 stability.

Main Results:

• Aberrant IGF2BP3 expression was significantly associated with poor prognosis in NSCLC patients.
• IGF2BP3 deficiency markedly inhibited NSCLC cell proliferation and tumor growth both in vitro and in vivo.
• IGF2BP3 was found to positively regulate S-Phase Kinase Associated Protein 2 (SKP2) expression by stabilizing its mRNA in an m6A-dependent manner.
• USP10 was identified as a novel DUB that deubiquitinates IGF2BP3, thereby increasing its protein levels and promoting proteasomal degradation inhibition.

Conclusions:

• IGF2BP3 serves as a critical oncogene in NSCLC, promoting tumor growth and progression.
• The IGF2BP3/SKP2 axis represents a potential therapeutic target in NSCLC.
• USP10-mediated stabilization of IGF2BP3 is a key regulatory mechanism contributing to oncogenesis in NSCLC.