BPTF transduces MITF-driven prosurvival signals in melanoma cells

Abstract

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...

BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits

“…Combined with the previous reports that BPTF is required for the establishment of the anterior-posterior axis of the mouse embryo during the earliest stages of development [11] and mediates pro-oncogenic role in cancer progression, including melanoma and lung cancer [14] , [15] , [25] ,we deduced BPTF might play a critical role in the stemness maintenance of HCC. Initially, we observed the effect of BPTF knockdown on the ability of tumorsphere formation.…”

“…It is also reported to be essential in embryonic development [11] , [12] . BPTF has recently been found to affect tumor progression, especially melanoma survival, by activating oncogenic signaling directly or by synergizing with other key protein factors, such as c-MYC [13] , [14] , [15] . Its prognostic significance associated with EMT marker in colorectal carcinoma and HCC was also mentioned [16] , [17] .…”

The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer

“…BPTF is a component of the nucleosome remodeling factor (NURF) complex of the ISWI subfamily. BPTF expression has been shown to be increased in several cancer types and was associated with tumor progression and worse survival [147][148][149][150][151]. Although BPTF has been associated with deletions, amplifications, and mutations in PDAC (Table 1), functional studies on its role in PDAC are limited.…”

The Many Roles of MITF in Melanoma

“…Thus, MITF-BCL2A1 is a lineage-specific oncogenic pathway in melanoma targetable by obatoclax, an inhibitor of all BCL2 family members, which is effective in melanoma treatment and improves the response to BRAF-directed therapy [33]. The antiapoptotic signals have been reported to be mediated by the MITF target BPTF protein that transduces key prosurvival role driven by MITF [34]. Another proapoptotic MITF target is ML-IAP/livin [35].…”