Editors' ChoiceCancer

CREBBP-mutated cancers HAT-tricked

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Science Translational Medicine  09 Dec 2015:
Vol. 7, Issue 317, pp. 317ec212
DOI: 10.1126/scitranslmed.aad8032

Genes that encode components of the chromatin remodeling complex are frequently mutated in cancer. CREBBP (CREB Binding Protein) is a chromatin modifier protein that is involved in multiple cellular processes and functions as a transcriptional cofactor and histone acetyltransferase (HAT). Histone acetylation allows the remodeling of chromatin into a relaxed state and facilitates active gene transcription. CREBBP mutations often result in loss of tumor-suppressive functions and are difficult to target therapeutically.

Ogiwara et al. performed functional gene screens in CREBBP-deficient cancer cells and identified EP300 as an essential gene required for the growth and survival of CREBBP-mutated cancer cells. EP300 is a structural and functional paralog of CREBBP. EP300 depletion was lethal in CREBBP- knockout cells but not in CREBBP wild-type cells. In CREBBP-knockout cells, EP300 depletion caused down-regulation of MYC by reducing histone acetylation in its promoter. This synthetic lethality was rescued by exogenous MYC expression, underscoring the connection between EP300 and MYC, a key oncogene that is overexpressed in the vast majority of human cancers and promotes cell growth and proliferation. In vivo studies demonstrated tumor shrinkage with EP300 inhibition in CREBBP-mutated lymphoma and lung cancer.

CREBBP mutations are found in many human cancers, including approximately 30% of lymphomas and 15% each of leukemias, lung cancers, and bladder cancers. The identification of EP300 as a critical factor for cell survival in the context of CREBBP deficiency provides a compelling rationale to explore EP300-targeted therapies for CREBBP-mutated cancers.

H. Ogiwara et al., Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality via apoptotic cell death due to abrogation of MYC expression. Cancer Discov. 10.1158/2159-8290.CD-15-0754 (2015). [Abstract]

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