Antitumor activity of selenopsammaplin A analog (SPA-10091-HCl) via histone methyltransferase DOT1L degradation and apoptosis induction in castration-resistant prostate cancer cells.

Abstract

Castrate-resistant prostate cancer (CRPC) is one of the most difficult cancers in men and is characterized by a poor prognosis and a high risk of metastasis. The overexpression of the disruptor of telomeric silencing 1-like (DOT1L), which is a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), has been related to poor outcomes in patients with CRPC. Therefore, targeting DOT1L is considered a potential therapeutic approach to overcome the significant medical challenges of CRPC. In our previous study, we designed selenopsammaplin A (SPA) analogs as non-nucleoside DOT1L inhibitors to suppress human breast cancer cell proliferation and metastasis. However, the antitumor activity and the precise underlying mechanism of SPA analogs in PC cells remain unclear. Herein, we administered SPA-10091-HCl, a DOT1L-targeting degrader, to effectively hinder the growth and DOT1L-mediated H3K79 methylation in CRPC (PC3 and DU145) cells. Mechanistically, SPA-10091-HCl selectively degrades DOT1L protein through the nuclear ubiquitin-proteasome pathway, thereby suppressing H3K79 methylation in CRPC cells. SPA-10091-HCl inhibits CRPC cell proliferation, migration, and invasion, with the E-cadherin expression upregulation and N-cadherin and vimentin expression downregulation. Additionally, prolonged SPA-10091-HCl treatment induced apoptosis by regulating apoptosis-associated protein expressions, including Poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-9, and Bcl-2. Moreover, SPA-10091-HCl effectively inhibited tumor growth in the PC3 cells-implanted xenograft mouse model without any overt toxicity. These results indicate SPA-10091-HCl as a potential candidate for further development as a chemotherapeutic agent against CRPC.