| Popis: |
Most cancer-related deaths are caused by recurrent metastatic disease with latency periods that range from years to even decades. This halt in disease progression is driven by cancer dormancy, a stage in which residual disease is present but remains asymptomatic before reawakening and often causes lethal forms of the disease. Cell fate decisions, such as the ones that underlie dormancy and reawakening of cancer cells, often require extensive epigenetic remodeling, which in turn allows for the expression of specific genetic programs that trigger cell fate decisions. Therefore, epigenetic remodeling is likely essential for the switch between dormant and proliferative states throughout the metastatic process. Here we focus on epigenetic regulator, histone H3.3 chaperone HIRA and its role in the proliferation-to-dormancy switch in breast cancer cells. In this study, we demonstrate that HIRA suppression leads to cell cycle arrest and induces canonical dormancy pathways via phosphorylation of p38 and induction of p27 expression. In addition, HIRA suppression triggers induction of stress-inducible transcription factors NRF2, MITF and ATF3 to enable the activation of genetic programs that maintain homeostasis and promote survival in dormant cells. Our data also portray that HIRA is suppressed in the well-established isogenic models of dormancy when compared to their metastatic counterparts. Altogether we present for the first-time histone chaperone HIRA as a major regulatory point of cell fate for disseminated cancer cells by controlling their transition between dormant and proliferative states, and therefore suggest HIRA as a novel and tremendously needed therapeutic target for metastatic breast cancer. Citation Format: Stanislav Drapela, Devesh Raizada, Ananya Mukherjee, Joanne Tejero, Didem Ilter, Jose Javier Bravo-Cordero, Ana P Gomes. HIRA is a master regulator of the proliferation-to-dormancy switch in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 65. |
