HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers

Mendillo, Marc L.; Santagata, Sandro; Koeva, Martina; Bell, George W.; Hu, Rong; Tamimi, Rulla M.; Fraenkel, Ernest; Ince, Tan A.; Whitesell, Luke; Lindquist, Susan

doi:10.1016/j.cell.2012.06.031

Cited by 616 publications

(914 citation statements)

References 68 publications

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“…For the heat-shock factor HSFA6B, we saw enrichment for high heat responses as expected, but also observed enrichment in mitotic functions (cell cycle and DNA replication; Figure 4, box 4). While plant HSFs have not been implicated in mitosis, a recent study of the human HSF1 indicates that this family may directly regulate cell division in proliferating cancer cells (Mendillo et al, 2012). For the C2H2 TF STZ, where mutants have enhanced tolerance to salt and abiotic stresses, we also saw enrichment in mitosis-related functions (Figure 4, box 4).…”

Section: The Arabidopsis Cistromementioning

confidence: 70%

Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape

O’Malley¹,

Huang²,

Song³

et al. 2016

Cell

368

482

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SUMMARYThe cistrome is the complete set of transcription factor (TF) binding sites (cis-elements) in an organism, while an epicistrome incorporates tissue-specific DNA chemical modifications and TFspecific chemical sensitivities into these binding profiles. Robust methods to construct comprehensive cistrome and epicistrome maps are critical for elucidating complex transcriptional networks that underlie growth, behavior, and disease. Here, we describe DNA affinity purification sequencing (DAP-seq), a high-throughput TF binding site discovery method that interrogates genomic DNA with in-vitro-expressed TFs. Using DAP-seq, we defined the Arabidopsis cistrome by resolving motifs and peaks for 529 TFs. Because genomic DNA used in DAP-seq retains 5-methylcytosines, we determined that >75% (248/327) of Arabidopsis TFs surveyed were methylation sensitive, a property that strongly impacts the epicistrome landscape. DAP-seq datasets also yielded insight into the biology and binding site architecture of numerous TFs, demonstrating the value of DAP-seq for cost-effective cistromic and epicistromic annotation in any organism.

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Section: The Arabidopsis Cistromementioning

confidence: 70%

Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape

O’Malley¹,

Huang²,

Song³

et al. 2016

Cell

368

482

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“…HSF1 now is understood to be a critical factor necessary for cancer cell maintenance, both by its ability to regulate HSP gene expression and by its ability to induce additional transcriptional programs (19). Thus it was tempting to explore the possible effects of PGC-1α expression on additional HSF1-dependent gene-expression programs beyond the HSR and to do so specifically in cancer cells.…”

Section: Pgc-1α Directly Regulates Hsf1-mediated Transcriptional Progmentioning

confidence: 99%

“…Consistent with its versatile functions in the regulation of numerous transcriptional programs, HSF1 also has been implicated in certain pathological conditions that include neurodegeneration and cancer (16,17). Although HSF1 may not be strictly required for normal cellular or organismal survival in mammals (18), the role of HSF1 in regulating non-HSR targets, including those related to DNA damage repair and the cell cycle, recently has emerged as critical for cancer cell survival (19)(20)(21). Thus, inhibiting the activity of HSF1 has been suggested as a potential anticancer therapeutic approach (22).…”

mentioning

confidence: 99%

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

Minsky

Roeder

2015

Proc. Natl. Acad. Sci. U.S.A.

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In recent years an extensive effort has been made to elucidate the molecular pathways involved in metabolic signaling in health and disease. Here we show, surprisingly, that metabolic regulation and the heat-shock/stress response are directly linked. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a critical transcriptional coactivator of metabolic genes, acts as a direct transcriptional repressor of heat-shock factor 1 (HSF1), a key regulator of the heat-shock/stress response. Our findings reveal that heatshock protein (HSP) gene expression is suppressed during fasting in mouse liver and in primary hepatocytes dependent on PGC-1α. HSF1 and PGC-1α associate physically and are colocalized on several HSP promoters. These observations are extended to several cancer cell lines in which PGC-1α is shown to repress the ability of HSF1 to activate gene-expression programs necessary for cancer survival. Our study reveals a surprising direct link between two major cellular transcriptional networks, highlighting a previously unrecognized facet of the activity of the central metabolic regulator PGC-1α beyond its well-established ability to boost metabolic genes via its interactions with nuclear hormone receptors and nuclear respiratory factors. Our data point to PGC-1α as a critical repressor of HSF1-mediated transcriptional programs, a finding with possible implications both for our understanding of the full scope of metabolically regulated target genes in vivo and, conceivably, for therapeutics. metabolism | transcription | stress response

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“…In this active conformation, HSF1 gains the ability to bind to consensus sequence motifs within the regulatory regions of its target genes known as heat shock elements to subsequently drive the transactivation of numerous protective HSPs. Importantly, although this role as a master regulator of the stress-inducible heat shock response has been established for many years, more recently it has become apparent that HSF1 can also drive transcriptional programs that facilitate and maintain the malignant phenotype of cancer cells (18,19).…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

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HSF1 Drives a Transcriptional Program Distinct from Heat Shock to Support Highly Malignant Human Cancers

Cited by 616 publications

References 68 publications

Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape

Cistrome and Epicistrome Features Shape the Regulatory DNA Landscape

Direct link between metabolic regulation and the heat-shock response through the transcriptional regulator PGC-1α

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

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