Targeting chaperone modifications: Innovative approaches to cancer treatment

Cancer and other chronic diseases are marked by alterations in the protein quality control system, affecting the posttranslational destiny of various proteins that regulate, structure, and catalyze cellular processes. Cellular chaperones, also known as heat shock proteins (HSPs), are pivotal in this system, performing protein triage that often determines the fate of proteins they bind to. Grasping the regulatory mechanisms of HSPs and their associated cofactors is crucial for understanding protein quality control in both healthy and diseased states. Recent research has shed light on the interactions within the protein quality control system and how post-translational modification govern protein interactions, function, and localization, which can drive or inhibit cell proliferation. This body of work encompasses critical elements of the heat shock response, including heat shock protein 70, heat shock protein 90, carboxyl-terminus of HSC70 interacting protein, and heat shock protein organizing protein. This review aims to synthesize these advancements, offering a holistic understanding of the system and its response when commandeered by diseases like cancer. We focus on the mechanistic shift in co-chaperone engagement-transitioning from heat shock protein organizing protein to carboxyl-terminus of HSC70 interacting protein in association with heat shock protein 70 and heat shock protein 90-which could influence cellular growth and survival pathways. A comprehensive examination of posttranslational modification-driven regulation within the protein quality control network is presented, highlighting the roles of activation factors, chaperones, and co-chaperones. Our insights aim to inform new strategies for therapeutically targeting diseases by considering the entire heat shock response system.