TY - JOUR
T1 - The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells
AU - Gallagher, Stuart J.
AU - Mijatov, Branka
AU - Gunatilake, Dilini
AU - Tiffen, Jessamy C.
AU - Gowrishankar, Kavitha
AU - Jin, Lei
AU - Pupo, Gulietta M.
AU - Cullinane, Carleen
AU - Prinjha, Rab K.
AU - Smithers, Nicholas
AU - Mcarthur, Grant A.
AU - Rizos, Helen
AU - Hersey, Peter
N1 - 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.
PY - 2014/11/5
Y1 - 2014/11/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84908575103&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/633004
U2 - 10.1038/jid.2014.243
DO - 10.1038/jid.2014.243
M3 - Article
C2 - 24906137
AN - SCOPUS:84908575103
SN - 0022-202X
VL - 134
SP - 2795
EP - 2805
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 11
ER -