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J Pathol. 2016 Nov;240(3):269-281. doi: 10.1002/path.4773. Epub 2016 Sep 27.

P/CAF mediates PAX3-FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma.

Author information

1
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3
Bionivid Technology Pvt Ltd, 401-4 AB Cross, 1st Main, Kasturi Nagar, Bangalore, India.
4
Department of Paediatrics, National University Hospital, Singapore.
5
Department of Pathology, KK Women and Children's Hospital, Singapore.
6
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
7
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. phsrt@nus.edu.sg.

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.

KEYWORDS:

cancer; epigenetics; histone acetyltransferase; post-translational modifications; stability

PMID:
27453350
DOI:
10.1002/path.4773
[Indexed for MEDLINE]

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