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KIAA1429/VIRMA promotes breast cancer progression by m6A-dependent cytosolic HAS2 stabilization

ABSTRACT: N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays important roles in many physiological and pathological processes, including the development and progression of cancer. RNA modification by m6A is regulated by methyltransferases, demethylases, and m6A-binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m6A regulatory proteins in breast cancer. We find that expression of KIAA1429/VIRMA, a component of the m6A methyltransferase complex, is upregulated in breast cancer tissue and correlates positively with poor survival. KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer tissues and cell lines, and shRNA-mediated knockdown inhibits breast cancer cell proliferation, migration, and invasion. Mechanistically, KIAA1429/VIRMA is shown to bind to the m6A-dependent RNA binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), leading to recruitment and stabilization of m6A-modified hyaluronan synthase 2 (HAS2) mRNA. HAS2 mRNA and KIAA1429/VIRMA mRNA levels correlate positively in breast cancer tissues, suggesting that the KIAA1429/VIRMA-IGF2BP3-HAS2 axis promotes breast cancer growth and contributes to poor prognosis.

SUBMITTER: Dr. Na Li

PROVIDER: S-SCDT-10_15252-EMBR_202255506 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Rationale: N6-methyladenosine (m6A) mRNA methylation is the most abundant chemical posttranscriptional modification in mRNA and is involved in the regulation of a number of biological processes. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) has recently been reported as having the capacity to recognize m6A sites in mRNA and plays a role in regulating mRNA metabolization. However, it is unclear which genes IGF2BP1 targets to identify m6A sites and what are their respective functions in endometrial cancer (EC). Methods: Quantitative PCR, western blot and immunohistochemistry were used to measure IGF2BP1 expression in EC cell lines and tissues. Xenograft experiments were performed to examine the in vivo role of IGF2BP1 in EC cell growth. RNA-binding protein immunoprecipitation sequencing, methylated RNA-binding protein immunoprecipitation sequencing and RNA-sequencing were also conducted to identify potential IGF2BP1 targets involved in EC regulation. Co-immunoprecipitation and mass spectrometry were used to identify IGF2BP1-interacting proteins. Results: IGF2BP1 expression increased in EC, and high expression of this protein correlated with poor prognosis. IGF2BP1 overexpression/knockdown can promote (and inhibit) cell proliferation and regulate the tumor cell cycle and cancer progression, both in vivo and in vitro. Mechanistically, IGF2BP1 can recognize m6A sites in the 3' untranslated region (3'UTR) of Paternally Expressed Gene 10 (PEG10) mRNA and recruits polyadenylate-binding protein 1 (PABPC1) to enhance PEG10 mRNA stability, which consequently promotes PEG10 protein expression. Additionally, it would appear that a large number of PEG10 proteins bind p16 and p18 gene promoter sequences, thereby repressing expression and accelerating the cell cycle. Conclusion: This investigation found that IGF2BP1 has a crucial role in the m6A-dependent regulatory mechanism for endometrial cancer. This study provides new insights into our understanding of disease progression and provides another potential route for understanding biological functions.

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KIAA1429/VIRMA promotes breast cancer progression by m6A-dependent cytosolic HAS2 stabilization

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