title: P/CAF mediates PAX3-FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma.
abstract: Alveolar rhabdomyosarcoma (ARMS) is an aggressive paediatric cancer of skeletal muscle with poor prognosis. A PAX3-FOXO1 fusion protein acts as a driver of malignancy in ARMS by disrupting tightly coupled but mutually exclusive pathways of proliferation and differentiation. While PAX3-FOXO1 is an attractive therapeutic target, no current treatments are designed to block its oncogenic activity. The present work shows that the histone acetyltransferase P/CAF (KAT2B) is overexpressed in primary tumours from ARMS patients. Interestingly, in fusion-positive ARMS cell lines, P/CAF acetylates and stabilizes PAX3-FOXO1 rather than MyoD, a master regulator of muscle differentiation. Silencing P/CAF, or pharmacological inhibition of its acetyltransferase activity, down-regulates PAX3-FOXO1 levels concomitant with reduced proliferation and tumour burden in xenograft mouse models. Our studies identify a P/CAF-PAX3-FOXO1 signalling node that promotes oncogenesis and may contribute to MyoD dysfunction in ARMS. This work exemplifies the therapeutic potential of targeting chromatin-modifying enzymes to inhibit fusion oncoproteins that are a frequent event in sarcomas. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Narendra
authors.initials: N
authors.lastname: Bharathy
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Sudha
authors.initials: S
authors.lastname: Suriyamurthy
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Rao
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Jin Rong
authors.initials: JR
authors.lastname: Ow
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Huey Jin
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: Bionivid Technology Pvt Ltd, 401-4 AB Cross, 1st Main, Kasturi Nagar, Bangalore, India.
authors.forename: Payal
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Bionivid Technology Pvt Ltd, 401-4 AB Cross, 1st Main, Kasturi Nagar, Bangalore, India.
authors.forename: Madavan
authors.initials: M
authors.lastname: Vasudevan
authors.affiliation: Department of Paediatrics, National University Hospital, Singapore.
authors.forename: Chetan Anil
authors.initials: CA
authors.lastname: Dhamne
authors.affiliation: Department of Pathology, KK Women and Children's Hospital, Singapore.
authors.forename: Kenneth Tou En
authors.initials: KT
authors.lastname: Chang
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Victor Lee Kwan
authors.initials: VL
authors.lastname: Min
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. phsrt@nus.edu.sg.
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D064593:Heterografts; D051379:Mice; D008819:Mice, Nude; D009132:Muscles / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D017570:MyoD Protein; D015514:Oncogene Proteins, Fusion; D051761:Paired Box Transcription Factors; D050880:p300-CBP Transcription Factors; C057363:MyoD1 myogenic differentiation protein; C471563:PAX3-FOXO1A fusion protein, human; C000620143:KAT2B protein, human; D000099224:p300-CBP-Associated Factor
keywords: cancer; epigenetics; histone acetyltransferase; post-translational modifications; stability