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  Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter

Ciato, D., Li, R., Garcia, J. L. M., Papst, L., D'Annunzio, S., Hristov, M., et al. (2019). Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter. Neuroendocrinology, 109(4), 362-373. doi:10.1159/000500200.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-FB34-6 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-FB35-5
Genre: Journal Article

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 Creators:
Ciato, Denis1, 2, Author              
Li, Ran, Author
Garcia, Jose Luis Monteserin, Author
Papst, Lilia3, Author
D'Annunzio, Sarah, Author
Hristov, Michael, Author
Tichomirowa, Maria A., Author
Belaya, Zhanna, Author
Rozhinskaya, Liudmila, Author
Buchfelder, Michael, Author
Theodoropoulou, Marily, Author              
Paez-Pereda, Marcelo3, 4, Author              
Stalla, Guenter Karl2, 4, 5, 6, Author              
Affiliations:
1Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_1607137              
2RG Clinical Neuroendocrinology, Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040301              
3Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
4Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              
5RG Günter Stalla, Clinical Neuroendocrinology, Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2040301              
6Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035296              

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 Abstract: Background: Cushing's disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress. Aims: Our objectives were: (1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment. Patients/Methods: We examined the expression of total and pSer(326)HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours. Results: We show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities. Conclusions: These data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.

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Language(s): eng - English
 Dates: 2019-11
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000497719000007
DOI: 10.1159/000500200
 Degree: -

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Title: Neuroendocrinology
Source Genre: Journal
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Publ. Info: Basel : S. Karger.
Pages: - Volume / Issue: 109 (4) Sequence Number: - Start / End Page: 362 - 373 Identifier: ISSN: 0028-3835
CoNE: https://pure.mpg.de/cone/journals/resource/954925428256