Please use this identifier to cite or link to this item: https://doi.org/10.1002/path.4773
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dc.titleP/CAF mediates PAX3–FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma
dc.contributor.authorBharathy, Narendra
dc.contributor.authorSuriyamurthy, Sudha
dc.contributor.authorRao, Vinay Kumar
dc.contributor.authorOw, Jin Rong
dc.contributor.authorLim, Huey Jin
dc.contributor.authorChakraborty, Payal
dc.contributor.authorVasudevan, Madavan
dc.contributor.authorDhamne, Chetan Anil
dc.contributor.authorChang, Kenneth Tou En
dc.contributor.authorVICTOR LEE KWAN MIN
dc.contributor.authorKundu, Tapas K
dc.contributor.authorRESHMA TANEJA
dc.date.accessioned2017-12-11T07:38:06Z
dc.date.available2017-12-11T07:38:06Z
dc.date.issued2016-11-01
dc.identifier.citationBharathy, 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
dc.identifier.issn00223417
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/137823
dc.description.abstractAlveolar 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.
dc.language.isoen
dc.publisherWiley
dc.subjectcancer
dc.subjectepigenetics
dc.subjecthistone acetyltransferase
dc.subjectpost-translational modifications
dc.subjectstability
dc.subjectAnimals
dc.subjectCarcinogenesis
dc.subjectCell Differentiation
dc.subjectCell Line, Tumor
dc.subjectCell Proliferation
dc.subjectDown-Regulation
dc.subjectEpigenomics
dc.subjectGene Silencing
dc.subjectHeterografts
dc.subjectMice
dc.subjectMice, Nude
dc.subjectMuscles
dc.subjectMyoD Protein
dc.subjectOligonucleotide Array Sequence Analysis
dc.subjectOncogene Proteins, Fusion
dc.subjectPaired Box Transcription Factors
dc.subjectRhabdomyosarcoma, Alveolar
dc.subjectSignal Transduction
dc.subjectp300-CBP Transcription Factors
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectProtein Processing, Post-Translational
dc.typeArticle
dc.contributor.departmentDEPT OF PATHOLOGY
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.description.doi10.1002/path.4773
dc.description.sourcetitleThe Journal of Pathology
dc.description.volume240
dc.description.issue3
dc.description.page269-281
dc.identifier.isiut000386692500005
dc.published.statePublished
dc.grant.fundingagencyMinistry of Education
dc.grant.fundingagencyNational Medical Research Council
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