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The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy

BACKGROUND: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. METHODS: The consequences of differential expression of...

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Autores principales: Dar, Altaf A., Nosrati, Mehdi, Bezrookove, Vladimir, de Semir, David, Majid, Shahana, Thummala, Suresh, Sun, Vera, Tong, Schuyler, Leong, Stanley P. L., Minor, David, Billings, Paul R., Soroceanu, Liliana, Debs, Robert, Miller, James R., Sagebiel, Richard W., Kashani-Sabet, Mohammed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555639/
https://www.ncbi.nlm.nih.gov/pubmed/25713167
http://dx.doi.org/10.1093/jnci/djv034
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author Dar, Altaf A.
Nosrati, Mehdi
Bezrookove, Vladimir
de Semir, David
Majid, Shahana
Thummala, Suresh
Sun, Vera
Tong, Schuyler
Leong, Stanley P. L.
Minor, David
Billings, Paul R.
Soroceanu, Liliana
Debs, Robert
Miller, James R.
Sagebiel, Richard W.
Kashani-Sabet, Mohammed
author_facet Dar, Altaf A.
Nosrati, Mehdi
Bezrookove, Vladimir
de Semir, David
Majid, Shahana
Thummala, Suresh
Sun, Vera
Tong, Schuyler
Leong, Stanley P. L.
Minor, David
Billings, Paul R.
Soroceanu, Liliana
Debs, Robert
Miller, James R.
Sagebiel, Richard W.
Kashani-Sabet, Mohammed
author_sort Dar, Altaf A.
collection PubMed
description BACKGROUND: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. METHODS: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided. RESULTS: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents. CONCLUSIONS: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.
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spelling pubmed-45556392015-09-02 The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy Dar, Altaf A. Nosrati, Mehdi Bezrookove, Vladimir de Semir, David Majid, Shahana Thummala, Suresh Sun, Vera Tong, Schuyler Leong, Stanley P. L. Minor, David Billings, Paul R. Soroceanu, Liliana Debs, Robert Miller, James R. Sagebiel, Richard W. Kashani-Sabet, Mohammed J Natl Cancer Inst Article BACKGROUND: Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we explore the oncogenic effects of BPTF in melanoma. METHODS: The consequences of differential expression of BPTF were explored using shRNA-mediated knockdown in several melanoma cell lines. Immunoblotting was used to assess the expression of various proteins regulated by BPTF. The functional role of BPTF in melanoma progression was investigated using assays of colony formation, invasion, cell cycle, sensitivity to selective BRAF inhibitors, and in xenograft models of melanoma progression (n = 12 mice per group). The biomarker role of BPTF in melanoma progression was assessed using fluorescence in situ hybridization and immunohistochemical analyses. All statistical tests were two-sided. RESULTS: shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF copy number (mean ≥ 3) was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival P = .03, and disease-specific survival P = .008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell subclones, indicating the continued presence of drug-responsive subclones within tumors demonstrating overall resistance to anti-BRAF agents. CONCLUSIONS: These studies demonstrate multiple protumorigenic functions for BPTF and identify it as a novel target for anticancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF. Oxford University Press 2015-02-24 /pmc/articles/PMC4555639/ /pubmed/25713167 http://dx.doi.org/10.1093/jnci/djv034 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Article
Dar, Altaf A.
Nosrati, Mehdi
Bezrookove, Vladimir
de Semir, David
Majid, Shahana
Thummala, Suresh
Sun, Vera
Tong, Schuyler
Leong, Stanley P. L.
Minor, David
Billings, Paul R.
Soroceanu, Liliana
Debs, Robert
Miller, James R.
Sagebiel, Richard W.
Kashani-Sabet, Mohammed
The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title_full The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title_fullStr The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title_full_unstemmed The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title_short The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
title_sort role of bptf in melanoma progression and in response to braf-targeted therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555639/
https://www.ncbi.nlm.nih.gov/pubmed/25713167
http://dx.doi.org/10.1093/jnci/djv034
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