Histone acetyltransferase PCAF is required for Hedgehog-Gli-dependent transcription and cancer cell proliferation.

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 aberrant Hh-Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh-Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found 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. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh-Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma.

• Authors: Martina Malatesta, Cornelia Steinhauer, Faizaan Mohammad, Deo P Pandey, Massimo Squatrito, Kristian Helin
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 20 Pg. 6323-33 (Oct 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23943798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• GLI1 protein, human
• Hedgehog Proteins
• RNA, Small Interfering
• Transcription Factors
• Zinc Finger Protein GLI1
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Animals
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Glioblastoma (enzymology, genetics, metabolism, pathology)
• Hedgehog Proteins (biosynthesis, genetics, metabolism)
• Humans
• Medulloblastoma (enzymology, genetics, metabolism, pathology)
• Mice
• NIH 3T3 Cells
• Promoter Regions, Genetic
• RNA, Small Interfering
• Signal Transduction
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Transfection
• Zinc Finger Protein GLI1
• p300-CBP Transcription Factors (genetics, metabolism)