m6A reader HNRNPA2B1 destabilization of ATG4B regulates autophagic activity, proliferation and olaparib sensitivity in breast cancer

Abstract

N⁶-methyladenosine RNA (m⁶A) is the most extensive epigenetic modification in mRNA and influences tumor progression. However, the role of m⁶A regulators and specific mechanisms in breast cancer still need further study. Here, we investigated the significance of the m⁶A reader HNRNPA2B1 and explored its influence on autophagy and drug sensitivity in breast cancer. HNRNPA2B1 was selected by bioinformatics analysis, and its high expression level was identified in breast cancer tissues and cell lines. HNRNPA2B1 was related to poor prognosis. Downregulation of HNRNPA2B1 reduced proliferation, enhanced autophagic flux, and partially reversed de novo resistance to olaparib in breast cancer. ATG4B was determined by RIP and MeRIP assays as a downstream gene of HNRNPA2B1, by which recognized the m⁶A site in the 3'UTR. Overexpression of ATG4B rescued the malignancy driven by HNRNPA2B1 in breast cancer cells and increased the olaparib sensitivity. Our study revealed that the m⁶A reader HNRNPA2B1 mediated proliferation and autophagy in breast cancer cell lines by facilitating ATG4B mRNA decay and targeting HNRNPA2B1/m⁶A/ATG4B might enhance the olaparib sensitivity of breast cancer cells.

Keywords: Autophagy; Breast cancer; HNRNPA2B1; N(6)-methyladenosine RNA; Olaparib.