The heat shock response, heat shock genes and proteins, heat shock transcription factor HSF1 and cancer

The stress or heat shock response (HSR) is a key mechanism for maintaining cellular proteostasis under conditions of heat or other proteotoxic stress. The response encompasses increased expression of so-called heat shock proteins (HSPs), molecular chaperones that reduce aggregation of misfolded proteins and promote their refolding or disposal (1,2). Activation of the HSR is triggered by protein damage that occurs in cells exposed to excessive but non-lethal heat or to chemicals or other conditions that cause proteins to become denatured (3,4).

The master regulator of the mammalian HSR is heat shock transcription factor 1 (HSF1) (5,6). In the absence of a stress, HSF1 is predominantly present in cells in an inactive, hetero-oligomeric complex comprising HSP90 and co-chaperones (7-10). Several additional proteins are known or inferred to bind HSF1 or HSF1 complex, including CHIP (11), HDAC6 (12,13), p97/VCP (12,13), DAXX (14), 14-3-3 (15), FILIP-1L (16) and HSBP1 (17). More recently, this list was expanded considerably by Fujimoto et al. and, most notably, now includes ATF1 and RPA1, which proteins interact with the HSF1 DNA-binding domain (18,19).

Stress-mediated activation of HSF1 and maintenance of the factor in an active form involves a multitude of events. An early event is the dissociation of HSP90 or HSP90 complex from the inactive HSF1 complex and the consequential homo-trimerization of HSF1 (7,20). HSF1 trimers are capable of specifically binding to so-called heat shock elements (HSE) present in promoters of target genes. However, whether the latter HSF1 trimers are also transactivation-competent appears to depend in part on whether they are capable of escaping re-association with HSP90 and/or HSP70 (21,22). Transcriptional activity of HSF1 will also depend on DAXX as well as on its phosphorylation status (14, 23-25). Recruitment of HSF1 to target promoters in response to a stress is mediated by ATF1/CREB (19). ATF1/CREB regulates the stress-induced HSF1 transcription complex that includes BRG1 chromatin-remodeling complex and p300/CBP. The former complex promotes an active chromatin state in the promoters, whereas p300/CBP accelerates the shutdown of HSF1 DNA-binding activity as well as stabilizes HSF1 against proteasomal degradation during recovery from stress (19,26). This shutdown is counteracted by SIRT1-mediated deacetylation (27).

Beyond the regulation of typical HSR genes such as HSP genes, activated HSF1 influences the activities of genes related to a variety of basic cellular processes. This HSF1-induced program may facilitate oncogenic transformation and maintenance of a malignant phenotype (28-33). Dai and colleagues demonstrated that genetic elimination of HSF1 protects mice from tumors induced by mutations in the RAS oncogene or a hot spot mutation in tumor suppressor gene P53 and that ablation of HSF1 by RNA interference is cytotoxic to various cancer cell lines (31). Work by others in different in vitro and in vivo cancer models permitted the generalization of these findings (34-37). Consistent with the dependence of many cancers on HSF1 activity is the observation of elevated nuclear levels of HSF1 in a high proportion of breast cancer samples from in situ and invasive breast carcinomas obtained from 1841 participants (38). High levels of HSF1 were correlated with poor survival. A subsequent study found high levels of nuclear HSF1 to be common in a wide range of cancers (30). These findings propound HSF1 as a promising new cancer therapeutic target.

Adapted from Vilaboa et al (2017) Nucleic Acids Res 45: 5797-817.

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