Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

Антонова, А. В.; Hummel, Barbara; Khavaran, Ashkan; Redhaber, Desiree Melanie; Aprile-Garcia, Fernando; Rawat, Prashant; Gundel, Kathrin; Schneck, Megan; Hansen, Erik C; Mitschke, Jan; Mittler, Gerhard; Miething, Cornelius; Sawarkar, Ritwick

doi:10.1016/j.celrep.2019.09.084

Cited by 23 publications

(15 citation statements)

References 110 publications

(118 reference statements)

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“…5, H and I, Table 3). The nuclear role of HSP90, including modulation of transcription, chromatin remodeling and DNA damage, has been described in several studies (Antonova et al, 2019;Trepel et al, 2010). Added to our previous findings (Fig.…”

Section: Patient-derived Organotypic Cultures (Pdoc) Are Sensitive Tosupporting

confidence: 69%

“…Although HSP90 is primarily a cytoplasmic protein, several studies have described its role in nuclear events such as transcriptional processes, chromatin remodeling and DNA damage (Antonova et al, 2019;Trepel et al, 2010). Moreover, increased nuclear HSP90 correlated positively with poor survival and distant metastasis in NSCLC patients (Su et al, 2016).…”

Section: Brain Metastases Are Positive For Hsp90mentioning

confidence: 99%

See 1 more Smart Citation

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

Zhu¹,

Yebra²,

Retana³

et al. 2020

Preprint

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Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

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Section: Patient-derived Organotypic Cultures (Pdoc) Are Sensitive Tosupporting

confidence: 69%

Section: Brain Metastases Are Positive For Hsp90mentioning

confidence: 99%

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

Zhu¹,

Yebra²,

Retana³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Cytosol HSP90 can interact with CDC37 to facilitate colorectal cancer progression 24 . Nuclear HSP90 is reported to regulate cell growth-related genes in erythroleukemic cells by stabilizing the transcription factor HCFC1 25 . Mitochondrial HSP90 contributes to vascular remodeling in pulmonary arterial hypertension 26 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics

Zhou

Huo

et al. 2021

Oncogenesis

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challenges in the clinical management of PDAC. In this study, we performed single-cell RNA sequencing to characterize PDAC tumors from KPC mice. Functional studies and clinical analysis showed that PDAC cluster 2 cells with highly Hsp90 expression is much more aggressive than the other clusters. Genetic and pharmacologic inhibition of Hsp90 impaired tumor cell growth both in vitro and in vivo. Further mechanistic study revealed that HSP90 inhibition disrupted the interaction between HSP90 and OPA1, leading to a reduction in mitochondrial cristae amount and mitochondrial energy production. Collectively, our study reveals that HSP90 might be a potential therapeutic target for PDAC.

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“…Hsp90 is down regulated by miR-27a and by PADI3 and PLK3. ©Biomedical Informatics (2020) Current scientific knowledge does not allow us to reconstruct an accurate regulation network and this represents a limitation to the understanding of the functioning of the system, to find the stimuli that up-or down-regulate Hsp90, to know how combine chaperone inhibition, to realize the drug resistance mechanisms .In addition to the experimental approaches, the large amount of expression data present in the public databases should also be analysed more accurately to obtain new information, as was done using interesting approaches [13][14][15][16]. Overall, insights into the molecular mechanisms of Hsp90 regulatory pathway are necessary for the definition of more reliable therapeutic targets for the inhibition of Hsp90 functions in cancers.…”

Section: Introductionmentioning

confidence: 99%

Gaining new insights on the Hsp90 regulatory network

Piva¹

2020

Bioinformation

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The heat shock protein Hsp90 is a molecular chaperon that uses ATP and interacts with various co-chaperone proteins, acting as adapters, in order to carry out the maturation of its target proteins. In physiological conditions, the heat shock proteins (HSPs) favour posttranslational modification, protein folding and sub-cellular transport of their "client" proteins. In stress conditions, many misfolded proteins accumulate exposing their hydrophobic residues and these are recognized by HSPs which prevent the aggregation and favour the correct folding. In case this is no longer possible, HSPs mediate elimination of such misfolded proteins, mainly by ubiquitin-proteasome system.

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Heat-Shock Protein 90 Controls the Expression of Cell-Cycle Genes by Stabilizing Metazoan-Specific Host-Cell Factor HCFC1

Abstract: Highlights d Comprehensive genetic and physical interactome of nuclear HSP90 in human cells d HSP90 stabilizes HCFC1 complex at chromatin to drive cellcycle gene expression d Synergistic killing of cancer cells by simultaneous inhibition of HSP90 and HCFC1

Cited by 23 publications

References 110 publications

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics

Gaining new insights on the Hsp90 regulatory network

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