Abstract 2666: ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress

The 70 kDa heat shock proteins (Hsp70s) are a family of ubiquitously expressed intracellular proteins that are required for the maintenance of protein homeostasis. Hsp70 is highly induced in response to cellular stressors, including oxidative stress, hyperthermia, hypoxia and changes in pH, contributing to cellular resistance to stress-induced cell death. Most tumor cells, which live under continuous stress conditions, express elevated levels of Hsp70 to combat these harsh conditions and suppress apoptosis. During cellular stress, Hsp70 maintains protein homeostasis through two opposing mechanisms: protein refolding and degradation. However, the mechanisms by which Hsp70 balances these opposing functions under stress conditions remain unknown. Here, we demonstrate that Hsp70 preferentially facilitates protein refolding after stress, gradually switching to protein degradation via a mechanism dependent on ARD1-mediated Hsp70 acetylation. During the early stress response, Hsp70 is immediately acetylated by ARD1 at K77, and the acetylated Hsp70 binds to the co-chaperone Hop to allow protein refolding. Thereafter, Hsp70 is deacetylated and binds to the ubiquitin ligase protein CHIP to complete protein degradation during later stages. In addition, this switch is essential for the maintenance of protein homeostasis and ultimately rescues cancer cells from stress-induced cell death. Therefore, ARD1-mediated Hsp70 acetylation is a key regulatory mechanism that enables Hsp70-expressing cancer cells to be more resistant to proteotoxic stress, and regulation of Hsp70 K77 acetylation might be helpful to cancer treatment. Note: This abstract was not presented at the meeting. Citation Format: Ji Hae Seo, So-Jin Shin, Jin Young Kim, Seungmee Lee, Hyewon Chung, Chi-Heum Cho. ARD1-mediated Hsp70 acetylation protects cancer cells against the cellular stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2666.