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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 Elements |
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