Targeting the dynamic HSP90 complex in cancer

Abstract

The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.

Figure 1 |. The HSP90 chaperone cycle.

Although molecular chaperone heat shock protein 90 (HSP90) samples multiple conformations in the absence of ATP or other factors, current models propose that ATP binding and hydrolysis, as well as a precisely sequenced interaction with an array of co-chaperones, subtly shift the conformational equilibrium, presumably by lowering the energy barrier between certain conformations, thus providing directionality to the HSP90 cycle^,,. ATP binding to the undimerized (open) amino terminal (N) domain of HSP90 promotes repositioning of a ‘lid’ segment (red) that leads to transient dimerization of the N domains. Subsequent structural rearrangements result in the ‘closed and twisted’ conformation of HSP90 that is committed to ATP hydrolysis. Binding of the co-chaperone activator of HSP90 ATPase 1 (AHA1) enhances the rate of ATP hydrolysis-dependent HSP90 cycling by increasing the rate of the conformational alterations that result in the acquisition of ATPase competence. The dashed arrow reflects the difficulty of HSP90 in achieving the ATPase-competent conformation in the absence of AHA1. The co-chaperones STIP1 (also known as p60H0P) and cell division cycle 37 homologue (CDC37), and N domain-binding HSP90 inhibitors, exert an opposite effect to that of AHA1 by preventing the initial structural changes necessary for N domain dimerization. Prostaglandin E synthase 3 (PTGES3; also known as p23) slows the ATPase cycle by stabilizing the closed conformation that is committed to ATP hydrolysis. C, carboxy-terminal domain; M, middle domain; P., inorganic phosphate.

Figure 2 |. Co-chaperones and post-translational modifications modulate HSP90 chaperone activity.

Numerous co-chaperones assist heat shock protein 90 (HSP90) in its chaperone activity. Co-chaperones modulate HSP90 ATPase activity and so determine the rate of chaperone cycling (for example, cell division cycle 37 homologue (CDC37), activator of HSP90 ATPase 1 (AHA1), p23 and STIP1 (also known as p60HOP)), recruit certain classes of client proteins to HSP90, and/or participate in chaperoning specific categories of clients (such as CDC37, STIP1,TAH1, PIH1, suppressor of G2 allele of SKP1 (SUGT1; also known as SGT1), FKBP51 and FKBP52) and post-translationally modify HSP90 itself, its co-chaperones and its client proteins (such as PP5 and CHIP). Post-translational modifications profoundly affect HSP90 function by affecting co-chaperone and client interaction, ATP binding and ATP hydrolysis. The three major regulatory post-translational modifications are phosphorylation, acetylation and S-nitrosylation. An updated list of HSP90-interacting co-chaperones and HSP90-dependent client proteins can be found at the Picard laboratory website (see Further information) maintained by the laboratory of D. Picard, University of Geneva, Switzerland.

Figure 3 |. HSP90 modulates nuclear events.

Four examples of the effect of heat shock protein 90 (HSP90) on nuclear events are shown. a | The androgen receptor (AR) exemplifies the importance of HSP90 in steroid hormone receptor (SHR) function. b | The importance of HSP90 in regulating heat shock transcription factor 1 (HSF1) activity is also shown. c | The effect of HSP90 on SMYD3-mediated histone methylation and its effect on the transcription of cancer-associated genes, such as NKX, WNT and C/EBP. d | An HSP90–BCL6 complex suppresses the transcription of several tumour suppressor genes and contributes to tumorigenesis. ATR, ataxia telangiectasia and Rad3-related; DHT, dihydrotestosterone; HRE, hormone response element; HSE, heat shock element; P, phosphorylation; PSA, prostate-specific antigen; RNA Pol II, RNA polymerase II.