LncRNA H19 Regulates Breast Cancer DNA Damage Response and Sensitivity to PARP Inhibitors via Binding to ILF2

Abstract

Although DNA damage repair plays a critical role in cancer chemotherapy, the function of lncRNAs in this process remains largely unclear. In this study, in silico screening identified <i>H19</i> as an lncRNA that potentially plays a role in DNA damage response and sensitivity to PARP inhibitors. Increased expression of <i>H19</i> is correlated with disease progression and with a poor prognosis in breast cancer. In breast cancer cells, forced expression of <i>H19</i> promotes DNA damage repair and resistance to PARP inhibition, whereas <i>H19</i> depletion diminishes DNA damage repair and increases sensitivity to PARP inhibitors. <i>H19</i> exerted its functional roles via direct interaction with ILF2 in the cell nucleus. <i>H19</i> and ILF2 increased BRCA1 stability via the ubiquitin-proteasome proteolytic pathway via the <i>H19</i>- and ILF2-regulated BRCA1 ubiquitin ligases HUWE1 and UBE2T. In summary, this study has identified a novel mechanism to promote BRCA1-deficiency in breast cancer cells. Therefore, targeting the <i>H19</i>/ILF2/BRCA1 axis might modulate therapeutic approaches in breast cancer.