Abstract 4779: IL-6/STAT3 signaling mediates MYB dysregulation in prostate cancer: Implications for aggressive disease progression and racial disparities

Abstract We have previously reported a role for MYB in the progression, aggressiveness, and therapy resistance of prostate cancer. Notably, we also observed racially disparate MYB expression, with higher levels being present in prostate cancer from Black patients, correlating with advanced tumor grade and shorter time to biochemical recurrence. In this study, we investigated the molecular mechanisms underlying MYB dysregulation in prostate cancer that could potentially be linked to its higher levels in Black patients. We found that serum levels of IL-6 were significantly elevated in Black patients with prostate cancer, and treatment of prostate cancer cell lines with IL-6 resulted in a dose- and time-dependent upregulation of MYB expression. IL-6-induced MYB upregulation was abolished when cells were pre-treated with either an IL-6 neutralizing antibody (Tocilizumab) or a STAT3 inhibitor (Stattic). Notably, AR-negative cell lines exhibited high basal MYB expression, which was slightly reduced by Tocilizumab treatment but drastically reduced upon STAT3 inhibition, suggesting that it is a significant regulator of MYB overexpression in prostate cancer. Chromatin immunoprecipitation (ChIP) analysis revealed increased STAT3 binding to the MYB in the first intronic region, following IL-6 treatment, which was reduced upon pre-treatment with Tocilizumab or Stattic. Additionally, in this region, we observed enhanced recruitment of CDK9, a key component of the P-TEFb complex, which is shown to facilitate the release of the MYB transcriptional pause through Ser2 phosphorylation in the c-terminal domain of RNA polymerase II. Pre-treatment of prostate cancer cells with a CDK9 inhibitor also attenuated IL-6-induced MYB expression. Finally, silencing MYB or treating cells with a CDK9 inhibitor significantly impaired IL-6-mediated proliferation, migration, and invasion of prostate cancer cells. These findings establish IL-6/STAT3 signaling as a critical regulator of MYB expression in prostate cancer, highlighting its potential role in prostate cancer pathogenesis and racial disparities. Citation Format: Vinayaraj Ellu Valappil, Shashi Anand, Kunwar Somesh Vikramdeo, Ranjana Mitra, Seema Singh, Ajay P. Singh. IL-6/STAT3 signaling mediates MYB dysregulation in prostate cancer: Implications for aggressive disease progression and racial disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4779.