Inhibition of Heat Shock-Induced H3K9ac Reduction Sensitizes Cancer Cells to Hyperthermia

Abstract

Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. KEAP1 and DPP7 as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment

“…The application of hyperthermia as a cancer treatment modality is highly esteemed due to its non-toxic and safety, thus establishing itself as an green therapeutic method. 23 The blood flow is believed to facilitate the dissipation of heat from the surrounding tissues of the blood vessels, thereby impeding the attainment of the required level of heating in hyperthermia. 24 However, tumor tissues exhibit aberrant blood vessels and a sluggish blood flow rate, which attenuates the local tissue’s capacity for heat dissipation and enables effective heat accumulation during hyperthermia.…”