The Role of BPTF in Melanoma Progression and in Response to BRAF-Targeted Therapy
Autor: | Robert J. Debs, Mohammed Kashani-Sabet, Stanley P. L. Leong, Liliana Soroceanu, Vladimir Bezrookove, David de Semir, Vera Sun, James R. Miller, Shahana Majid, Mehdi Nosrati, Schuyler Tong, David R. Minor, Altaf A. Dar, Suresh Thummala, Richard W. Sagebiel, Paul R. Billings |
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Rok vydání: | 2015 |
Předmět: |
Proto-Oncogene Proteins B-raf
Cancer Research Indoles Skin Neoplasms medicine.medical_treatment Immunoblotting Gene Dosage Mice Nude Antineoplastic Agents Nerve Tissue Proteins Biology Real-Time Polymerase Chain Reaction Article Targeted therapy Mice Oximes Biomarkers Tumor medicine Animals Gene silencing Molecular Targeted Therapy Vemurafenib Melanoma neoplasms In Situ Hybridization Fluorescence Sulfonamides Gene knockdown Imidazoles Antigens Nuclear Cell cycle medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays 3. Good health Gene Expression Regulation Neoplastic Mice Inbred C57BL Oncology Tumor progression Mutation Disease Progression Cancer research Female Transcription Factors medicine.drug |
Zdroj: | JNCI Journal of the National Cancer Institute |
ISSN: | 1460-2105 0027-8874 |
Popis: | 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. |
Databáze: | OpenAIRE |
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