The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells

Stuart J Gallagher; Branka Mijatov; Dilini Gunatilake; Jessamy C Tiffen; Kavitha Gowrishankar; Lei Jin; Gulietta M Pupo; Carleen Cullinane; Rab K Prinjha; Nicholas Smithers; Grant A McArthur; Helen Rizos; Peter Hersey

doi:10.1038/jid.2014.243

The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells

J Invest Dermatol. 2014 Nov;134(11):2795-2805. doi: 10.1038/jid.2014.243. Epub 2014 Jun 6.

Affiliations

¹ Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia.
² Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
³ Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Epinova Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.
⁵ Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, New South Wales, Australia; Melanoma Institute of Australia, North Sydney, New South Wales, Australia. Electronic address: [email protected].

PMID: 24906137
DOI: 10.1038/jid.2014.243

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Apoptosis Regulatory Proteins / metabolism*
Bcl-2-Like Protein 11
Caspases / metabolism
Cell Cycle Checkpoints / drug effects
Cell Cycle Proteins
Cell Line
Cell Line, Tumor
Cell Survival
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Mutational Analysis
Epigenesis, Genetic*
Female
GTP Phosphohydrolases / metabolism
Gene Expression Regulation, Neoplastic*
Heterocyclic Compounds, 4 or More Rings / chemistry*
Humans
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / metabolism*
Membrane Proteins / metabolism*
Mice
Mice, Inbred NOD
Monomeric GTP-Binding Proteins / metabolism
Neoplasm Transplantation
Nuclear Proteins / metabolism
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins B-raf / metabolism
Transcription Factors / metabolism
Transcriptome

Substances

Apoptosis Regulatory Proteins
BCL2L11 protein, human
BRD4 protein, human
Bcl-2-Like Protein 11
Bcl2l11 protein, mouse
CDKN1A protein, human
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
GSK1210151A
Heterocyclic Compounds, 4 or More Rings
Membrane Proteins
Nuclear Proteins
Proto-Oncogene Proteins
Transcription Factors
BRAF protein, human
Proto-Oncogene Proteins B-raf
Caspases
GTP Phosphohydrolases
NRAS protein, human
Monomeric GTP-Binding Proteins
Nras protein, mouse