HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

Abstract

Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Escalating doses of HSP90 inhibitors in combination with a BRAF inhibitor (vemurafenib) was shown to increase the overall survival of BRAF V600E-mutated melanoma patients [99] [100]. As HSP90 inhibitors show a very broad spectrum of action [101], degradation of AhR can be optimized by targeting the co-chaperone protein p23. Down-regulation of the p23 protein triggers ubiquitination of AhR [102] and specific inhibition of p23 (ailanthone) shows important anticancer effects in vitro [103].…”

TRAP1 Regulates Wnt/β-Catenin Pathway through LRP5/6 Receptors Expression Modulation

“…While the evidence that TRAP1 protein network is responsible for reprogramming of DNA methylation events is a new finding, recent reports suggest a role for HSP90 as “epigenetic capacitor”. Indeed, HSP90 contributes to the phenotypic plasticity and modulates epigenetics by interacting with chromatin, chromatin regulators, and epigenetic effectors [ 36 ]. Furthermore, chromatin remodeling is at the crossroad between metabolism and gene expression as sit is a dynamic transcriptional mechanism highly responsive to external stimuli and environmental changes such as nutrient availability [ 37 ].…”

Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression

“…Due to their inhibitory effect, these oncometabolites can drive cellular transformation and oncogenesis. As potent inhibitors of TETs and JHDMs, their accumulation causes an epigenetic dysregulation due to DNA and histone hypermethylation and triggers a transcriptional program with downregulation of genes involved in suppression of metastasis and simultaneously promotes dedifferentiation, epithelial-mesenchymal transition (EMT), and invasiveness [55,61,62,63]. Loss-of-function mutations of SDH and FH enzymes cause the accumulation of, respectively, succinate and fumarate in different types of human malignancies.…”