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*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)
31 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2795-2805
Number of pages11
JournalJournal of Investigative Dermatology
Volume134
Issue number11
DOIs
Publication statusPublished - 5 Nov 2014
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2014. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Fingerprint Dive into the research topics of 'The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells'. Together they form a unique fingerprint.

  • Cite this

    Gallagher, S. J., Mijatov, B., Gunatilake, D., Tiffen, J. C., Gowrishankar, K., Jin, L., ... Hersey, P. (2014). The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells. Journal of Investigative Dermatology, 134(11), 2795-2805. https://doi.org/10.1038/jid.2014.243