The Functional Landscape of Hsp27 Reveals New Cellular Processes such as DNA Repair and Alternative Splicing and Proposes Novel Anticancer Targets

Abstract

Previously, we identified the stress-induced chaperone, Hsp27, as highly overexpressed in castration-resistant prostate cancer and developed an Hsp27 inhibitor (OGX-427) currently tested in phase I/II clinical trials as a chemosensitizing agent in different cancers. To better understand the Hsp27 poorly-defined cytoprotective functions in cancers and increase the OGX-427 pharmacological safety, we established the Hsp27-protein interaction network using a yeast two-hybrid approach and identified 226 interaction partners. As an example, we showed that targeting Hsp27 interaction with TCTP, a partner protein identified in our screen increases therapy sensitivity, opening a new promising field of research for therapeutic approaches that could decrease or abolish toxicity for normal cells. Results of an in-depth bioinformatics network analysis allying the Hsp27 interaction map into the human interactome underlined the multifunctional character of this protein. We identified interactions of Hsp27 with proteins involved in eight well known functions previously related to Hsp27 and uncovered 17 potential new ones, such as DNA repair and RNA splicing. Validation of Hsp27 involvement in both processes in human prostate cancer cells supports our system biology-predicted functions and provides new insights into Hsp27 roles in cancer cells.

The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation

“…However, unlike the UBR1 family, HUWE1 is a giant (450 kD) ubiquitin ligase, and in addition to the HECT ubiquitin ligase domain, it contains many protein-protein interaction motifs. Among the reported interactions, it is noteworthy that HUWE1 was identified as a component of the Hsp27 interactome [34]. This provides a possible explanation for the hydrophobic nature of the identified ‘degron’ on HUWE1 substrates.…”

The hallmarks of castration-resistant prostate cancers

“…Growing evidence show that AS of AR is a key capability of cancer cells to evade the normal activation of the pathway [136]. absence of Hsp27, strongly supports the involvement of Hsp27 in differential splicing events [98]. High-throughput analyses of PC samples have revealed more than 200 genes whose AS is differentially regulated.…”

“…Notably, Hsp27 belongs to the 1% of genes overexpressed during CR progression [94,95] and is associated with poor prognosis and treatment resistance [97]. We also recently demonstrated that Hsp27 is a multifunctional protein capable of interacting with a great number of partner proteins to protect cells from lethal conditions [98]. We showed that the Hsp27-interacting protein TCTP is involved in Hsp27 cytoprotection in CRPC [99].…”

Repair or destruction—an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis

“…Although HUWE1‐dependent degradation of unassembled proteins is linked to the Ub‐selective chaperone p97, the possible involvement of other chaperones engaged in recognizing and presenting misfolded HUWE1 targets is not addressed yet. A recent proteomic study identified HUWE1–Hsp27 interaction, which might link HUWE1 to chaperone‐dependent degradation of hydrophobic polypeptides .…”