ETS-1-activated LINC01016 over-expression promotes tumor progression via suppression of RFFL-mediated DHX9 ubiquitination degradation in breast cancers.

Long non-coding RNAs (lncRNAs) are key regulators during the development of breast cancer (BC) and thus may be viable treatment targets. In this study, we found that the expression of the long intergenic non-coding RNA 01016 (LINC01016) was significantly higher in BC tissue samples with positive lymph node metastasis. LINC01016, which is activated by the transcription factor ETS-1, contributes to the overt promotion of cell proliferation activity, enhanced cell migratory ability, S phase cell cycle arrest, and decreased apoptosis rate. By RNA pull-down assays and mass spectrometry analyses, we determined that LINC01016 competitively bound and stabilized DHX9 protein by preventing the E3 ubiquitin ligase RFFL from binding to DHX9, thereby inhibiting DHX9 proteasomal degradation. This ultimately led to an increase in intracellular DHX9 expression and activated PI3K/AKT signaling, with p-AKT, Bcl-2, and MMP-9 involvement. This is the first study to reveal that the LINC01016/DHX9/PI3K/AKT axis plays a critical role in the progression of BC, and thus, LINC01016 may serve as a potential therapeutic target for patients with BC.