The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and this histone mark is associated with activation of gene expression. DOT1L has a well-known role in MLL fusion leukemogenesis, however, its role in prostate cancer is yet to be elucidated. Here we show that DOT1L is overexpressed in many solid tumors including prostate cancer and is associated with a poor outcome. Genetic and chemical targeting of DOT1L showed a preferential loss in cell viability and colony formation in androgen receptor (AR)-signaling competent prostate cancer cells, including castration-resistant and enzalutamide-resistant cells. DOT1L inhibition reduced AR levels and upregulated enzymes involved in testosterone catabolism but only affected the expression of a subset of AR target genes. More importantly, loss of DOT1L selectively impaired telomere integrity by promoting telomere uncapping and shortening in AR-signaling competent cells. DOT1L inhibition also reduced the expression of telomerase and Shelterin complex genes including TRF2 and POT1. Recruitment of AR to telomeres and K79 methylation at sub-telomeric regions was also diminished. Consequently, loss of DOT1L leads to induction of Telomere dysfunction induced foci (TIF) and activates a cellular senescence program in these cells. Hence, these results provide compelling evidence for DOT1L inhibition as a novel therapeutic approach in advanced prostate cancers.

Citation Format: Rajita Vatapalli, Yara Rodriguez, Changsheng Zhao, Vinay Sagar, Jonathan Anker, Sahithi Pamarthi, Kenji Unno, Benedito Carneiro, Debabrata Chakravarti, Sarki Abdulkadir. Dot1l inhibition selectively impairs androgen receptor dependent prostate cancer growth through loss of telomere integrity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3687.