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

Dar, Altaf A.; Nosrati, Mehdi; Bezrookove, Vladimir; Semir, David de; Majid, Shahana; Thummala, Suresh; Sun, Vera; Tong, Schuyler; Leong, Stanley P. L.; Minor, David R.; Billings, Paul R.; Soroceanu, Liliana; Debs, Robert J.; Miller, James R.; Sagebiel, Richard W.; Kashani‐Sabet, Mohammed

doi:10.1093/jnci/djv034

Cited by 77 publications

(75 citation statements)

References 42 publications

(43 reference statements)

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“…Our prior analysis showed that BPTF activates the MAP kinase pathway by regulating ERK expression at the transcriptional level (11). Taken together, these studies demonstrate that BPTF is involved in multiple signaling pathways critical to melanoma proliferation and survival.…”

Section: Discussionmentioning

confidence: 74%

“…Recent studies identified an oncogenic role for BPTF in melanoma progression, and described a role both in the prediction and promotion of melanoma distant metastasis (11). BPTF mediated its proproliferative and pro-oncogenic effects by regulating the expression of prosurvival genes, such as BCL2, BCL-XL, and CCND2.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we identified a role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression (11). BPTF is the largest subunit of the nucleosome-remodeling factor, a key member of the imitation switch (ISWI) family of ATP-dependent chromatin-remodeling factors.…”

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confidence: 99%

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BPTF transduces MITF-driven prosurvival signals in melanoma cells

Dar

Majid

Bezrookove

et al. 2016

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

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Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression. melanoma | signaling cascade | oncogenes M icrophthalmia-associated transcription factor (MITF) is known to play a key role in melanocyte biology and progression. MITF performs these functions by activating transcription of many genes through interaction with the consensus DNA-binding sequence (CACGTG, termed E box) present on the promoters of target genes. MITF controls expression of several proteins required for melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerose (DCT) (1-3). In addition, MITF plays a critical role in melanocyte survival and serves as a lineagespecific oncogene in melanoma, as evidenced by its amplification in a subset of melanomas (4-6). MITF expression is regulated by several factors, including SOX-10, CREB, PAX3, LEF1, and ATF2 (7,8). MITF in turn regulates a plethora of genes, with its complex role in melanoma biology, as its overexpression has been shown to result in both proproliferative and antiproliferative stimuli (4, 5, 9, 10). Accordingly, verified targets of MITF include both genes that promote cell survival and block apoptosis, (e.g., CDK2, BCL2, DIAPH1, and TBX2), and genes that block cell cycle progression (e.g., CDKN2A and p21Cip1). Thus, although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are still poorly understood.Recently, we identified a role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression (11). BPTF is the largest subunit of the nucleoso...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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BPTF transduces MITF-driven prosurvival signals in melanoma cells

Dar

Majid

Bezrookove

et al. 2016

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

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“…BPTF is required for MAPK and PI3K/AKT signaling and the survival of lung cancer cells (46). BPTF is also important for cell proliferation through interaction with c-Myc in fibroblasts and melanoma cells (47, 48). Since MAPK, PI3K/AKT and c-Myc dependent pathways can regulate T cell function (49–51), it is plausible that one or more of these pathway(s) is perturbed in the absence of BPTF in T cells.…”

Section: Discussionmentioning

confidence: 99%

BPTF Is Essential for T Cell Homeostasis and Function

Wang

et al. 2016

The Journal of Immunology

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Bromodomain PHD Finger Transcription Factor (BPTF), a ubiquitously expressed ATP-dependent chromatin-remodeling factor, is critical for epigenetically regulating DNA accessibility and gene expression. While BPTF is important for the development of thymocytes, its function in mature T cells remains largely unknown. By specifically deleting BPTF from late DN3/DN4 stage of developing T cells, we found that BPTF was critical for the homeostasis of T cells via a cell intrinsic manner. In addition, BPTF was essential for the maintenance and function of Treg cells. Treg cell-specific BPTF deletion led to reduced Foxp3 expression, increased lymphocyte infiltration in the non-lymphoid organs and a systemic autoimmune syndrome. These findings therefore reveal a vital role for BPTF in T and Treg cell function and immune homeostasis.

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“…1 Clinical trials are underway evaluating inhibition of several members of the bromodomain and extra terminal family (BET) bromodomains (i.e, Brd2, 3, 4) in cancer, diabetes, and inflammation, supporting bromodomain modulation as a potential therapeutic approach. 2 The bromodomain PHD finger transcription factor, BPTF, is thought to play a significant role in melanoma, 3 leukemia, 4 colorectal, 5 and bladder cancer 6 . Both the PHD finger and bromodomain are important for chromatin binding.…”

Section: Introductionmentioning

confidence: 99%

Dual Screening of BPTF and Brd4 Using Protein-Observed Fluorine NMR Uncovers New Bromodomain Probe Molecules

et al. 2015

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Bromodomain-containing protein dysregulation is linked to cancer, diabetes, and inflammation. Selective inhibition of bromodomain function is a newly proposed therapeutic strategy. We describe a 19F NMR dual screening method for small molecule discovery using fluorinated tryptophan resonances on two bromodomain-containing proteins. The chemical shift dispersion of 19F resonances within fluorine-labeled proteins enables the simultaneous analysis of two fluorinated bromodomains by NMR. A library of 229 small molecules was screened against the first bromodomain of Brd4 and the BPTF bromodomain. We report the first small molecule selective for BPTF over Brd4, termed AU1. The Kd = 2.8 μM for AU1 which is active in a cell-based reporter assay. No binding is detected with Brd4. Three new Brd4 inhibitors with submicromolar affinity were also discovered. Brd4 hits were validated in a thermal stability assay and potency determined via fluorescence anisotropy. The speed, ease of interpretation, and low protein concentration needed for protein-observed 19F NMR experiments in a multi-protein format, offers a new method to discover and characterize selective ligands for bromodomain-containing proteins.

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

Cited by 77 publications

References 42 publications

BPTF transduces MITF-driven prosurvival signals in melanoma cells

BPTF transduces MITF-driven prosurvival signals in melanoma cells

BPTF Is Essential for T Cell Homeostasis and Function

Dual Screening of BPTF and Brd4 Using Protein-Observed Fluorine NMR Uncovers New Bromodomain Probe Molecules

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