Tailoring of Proteostasis Networks with Heat Shock Factors

Joutsen, Jenny; Sistonen, Lea

doi:10.1101/cshperspect.a034066

Cited by 78 publications

(63 citation statements)

References 143 publications

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“…Upon stress, misfolded proteins compete for chaperones and HSF1 is released, trimerizes and binds to HSEs. HSF1 is subject to multiple post-translational modifications, including phosphorylation, sumoylation, ubiquitination, and acetylation, which regulate DNA binding, transactivation of heat shock genes and degradation (Boyault et al 2007;Dayalan Naidu and Dinkova-Kostova 2017;Joutsen and Sistonen 2019;Li et al 2017;Pernet et al 2014). Whereas phosphorylation of residues in HSF1's regulatory domain was thought to be required for transactivational competence, more recent evidence points to a role in fine tuning of the heat shock response, including regulation of HSF1 binding to promoter elements (Budzynski et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

Kuta

Larochelle

Fernández

et al. 2020

Cell Stress and Chaperones

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Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUS P525L mutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

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Section: Introductionmentioning

confidence: 99%

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

Kuta

Larochelle

Fernández

et al. 2020

Cell Stress and Chaperones

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“…Instead, alterations in cell signaling pathways dependent on HSP activity may enable and promote oncogenesis [123,178]. HSF1 and HSPs are heavily post-translationally modified (reviewed in [36,[179][180][181]). In cancer, abnormal modification of HSPs could alter interactions with and regulation of HSF1, while an aberrant HSF1 modification states may drive malignant growth.…”

Section: Molecular Chaperone Feedback Interactionmentioning

confidence: 99%

“…A centrally positioned regulatory domain (RD), which is capable of sensing heat and activating transcription [35], is subject to extensive post-translational modifications and is believed to regulate an intramolecular fold of inactive HSF1 monomers between the HR-C and HR-A/B. The formation of an active HSF1 trimer, its binding to DNA, and transcriptional activation appear to be regulated by a combinatorial series of post-translational modifications [36]. It seems likely that the mechanisms of HSF1 activation, including the activity of upstream regulatory molecules, will differ qualitatively and quantitatively in transformed cells in which, instead of the acute and transient induction observed after stress, HSF1 becomes switched on chronically in a mechanism unlikely to involve acute proteotoxic stress [1,26,37,38].…”

Section: Introductionmentioning

confidence: 99%

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Prince

Lang

Guerrero-Gimenez

et al. 2020

Cells

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Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.

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“…HSF1 plays an important role in the initiation, promotion and progression of different types of cancer [9,10]. Knockdown of HSF1 signi cantly reduces tumor growth and prolongs survival when cells are exposured to various carcinogens [10][11][12]. Therefore, HSF1 has been recognized as a potential therapeutic target for antitumor therapy.…”

Section: Introductionmentioning

confidence: 99%

HSF2 is a Promising Prognostic Biomarker and is Correlated With Immune Infiltration in Hepatocellular Carcinoma

Han

Meng

Fan

et al. 2020

Preprint

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BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies and ranks as the second leading cause of cancer-related mortality worldwide. Heat shock factor 2 (HSF2) is a transcription factor that plays a critical role in development, particularly corticogenesis and spermatogenesis. However, studies on the expression and prognostic value of HSF2 and its association with tumor-infiltrating immune cells in HCC are still rare. MethodsThe TCGA, Oncomine, UALCAN, HCCDB and HPA databases were used to investigate HSF2 expression in HCC. Kaplan-Meier plotter, GEPIA and HCCDB databases were used to evaluate the association of HSF2 with the prognosis of HCC patients. Genetic alteration of HSF2 was examined by the cBioPortal database. The mechanism was investigated with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GESA), and the relationship between HSF2 expression and immune infiltration was explored through the TIMER database and CIBERSORT algorithm.Results In the present study, we found that HSF2 expression was significantly upregulated in HCC compared with normal liver tissues. High HSF2 expression was associated with poor survival in HCC patients. GO, KEGG and GESA analyses demonstrated that HSF2 was associated with various signaling pathways, including the immune response. Notably, HSF2 expression was significantly correlated with the infiltration levels of different immune cells. HSF2 expression also displayed a significant correlation with multiple immune marker sets in HCC. ConclusionsIn summary, we explored the clinical significance of HSF2 and provided a therapeutic basis for the early diagnosis, prognostic judgment, and immunotherapy of HCC.

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Tailoring of Proteostasis Networks with Heat Shock Factors

Cited by 78 publications

References 143 publications

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

HSF2 is a Promising Prognostic Biomarker and is Correlated With Immune Infiltration in Hepatocellular Carcinoma

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