Please use this identifier to cite or link to this item: https://doi.org/10.1002/path.4773
Title: P/CAF mediates PAX3–FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma
Authors: Bharathy, Narendra
Suriyamurthy, Sudha
Rao, Vinay Kumar
Ow, Jin Rong
Lim, Huey Jin
Chakraborty, Payal
Vasudevan, Madavan
Dhamne, Chetan Anil
Chang, Kenneth Tou En
VICTOR LEE KWAN MIN 
Kundu, Tapas K
RESHMA TANEJA 
Keywords: cancer
epigenetics
histone acetyltransferase
post-translational modifications
stability
Animals
Carcinogenesis
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
Down-Regulation
Epigenomics
Gene Silencing
Heterografts
Mice
Mice, Nude
Muscles
MyoD Protein
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Fusion
Paired Box Transcription Factors
Rhabdomyosarcoma, Alveolar
Signal Transduction
p300-CBP Transcription Factors
Gene Expression Regulation, Neoplastic
Protein Processing, Post-Translational
Issue Date: 1-Nov-2016
Publisher: Wiley
Citation: Bharathy, Narendra, Suriyamurthy, Sudha, Rao, Vinay Kumar, Ow, Jin Rong, Lim, Huey Jin, Chakraborty, Payal, Vasudevan, Madavan, Dhamne, Chetan Anil, Chang, Kenneth Tou En, VICTOR LEE KWAN MIN, Kundu, Tapas K, RESHMA TANEJA (2016-11-01). P/CAF mediates PAX3–FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma. The Journal of Pathology 240 (3) : 269-281. ScholarBank@NUS Repository. https://doi.org/10.1002/path.4773
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.
Source Title: The Journal of Pathology
URI: http://scholarbank.nus.edu.sg/handle/10635/137823
ISSN: 00223417
DOI: 10.1002/path.4773
Appears in Collections:Staff Publications

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