The Epigenetic Regulator I-BET151 Induces BIM-Dependent Apoptosis and Cell Cycle Arrest of Human Melanoma Cells

Abstract

Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. G1 cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.

Direct neuronal reprogramming: learning from and for development

“…In fact, the overexpression of the cell cycle activator Myc actually reduced the efficiency of fibroblast conversion to neuronal cells (Fishman et al, 2015). This supports the observation that BETbromodomain inhibitors enhance neuronal reprogramming mediated by small molecules (Hu et al, 2015;Zhang et al, 2015), as these compounds cause cell cycle arrest and inhibit Myc expression at transcriptional levels (Cheng et al, 2007;Delmore et al, 2011;Gallagher et al, 2014).…”

Bromodomain-Containing Protein 4

“…In cancer, p21 is a known target of BRD4, as many studies show increased p21 expression on BRD4 inhibition. 15,17,33 In these studies, they suggest that the BRD4 effect on p21 is through the transcription factor Myc. Nevertheless, we did not find a clear evidence of Myc regulation by BRD4 in PAH (data not shown), although it is known that Myc expression is increased in PAH.…”

“…Recent research described the implication of the newly characterized epigenetic readers bromodomain and extra terminal (BET) domain family in a range of cancers. [11][12][13][14][15] These BET domain proteins include bromodomain-containing protein 2 (BRD2), BRD3, BRD4, and bromodomain testis-specific protein. They bind to acetylated histone tails and other proteins via their tandem bromodomains 1 and 2.…”

Targeting BET Bromodomains for Cancer Treatment

“…In vivo, the progression of the A375 melanoma xenograft is inhibited by MS417 and the number of metastases is markedly reduced. I-BET151 also impairs melanoma cell proliferation in vitro and in vivo [75,76]. Downregulation of NF-κB target genes was evidenced, mainly linked to BRD2.…”

“…Treatment with JQ1 reduces proliferation of orthotopic glioblastoma models while downregulation of c-Myc and BCL2 is observed in cell lines derived from this tumor type [75]. Treatment with I-BET151 inhibits in vitro and in vivo growth of the U87MG model [78].…”