Abstract A19: The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation

Abstract

Abstract The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh-Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of an aberrant Hh-Gli signaling has thus emerged as an attractive target for anticancer therapy, however the mechanisms that mediate Hh-Gli signaling in vertebrates remain still poorly understood. Here, we show that the histone acetyltransferase (HAT) PCAF/KAT2B is an important regulator of the Hh pathway. Specifically, we demonstrate that PCAF depletion leads to an impairment of Hh activity and reduced expression of Hh target genes. Consequently, downregulation of PCAF in medulloblastoma and glioblastoma cell lines leads to decreased cell proliferation and increased apoptosis. Furthermore, we show that PCAF interacts with GLI1, the downstream effector in the Hh-Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Our study identifies the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, and we propose PCAF as a potential interesting novel therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. Citation Format: Martina Malatesta, Cornelia Steinhauer, Massimo Squatrito, Kristian Helin. The histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and proliferation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A19.