Your browser doesn't support javascript.
loading
ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.
Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R; Chen, Zhihua; Kumar-Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J; Mahajan, Nupam P.
Afiliação
  • Mahajan K; Tumor Biology Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
  • Malla P; Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
  • Lawrence HR; Chemical Biology Core, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
  • Chen Z; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
  • Kumar-Sinha C; Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Malik R; Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Shukla S; Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Kim J; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
  • Coppola D; Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
  • Lawrence NJ; Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA.
  • Mahajan NP; Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA. Electronic address: nupam.mahajan@moffitt.org.
Cancer Cell ; 31(6): 790-803.e8, 2017 06 12.
Article em En | MEDLINE | ID: mdl-28609657
ABSTRACT
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Histonas / Receptores Androgênicos / Regulação Neoplásica da Expressão Gênica / Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Tirosina Quinases / Histonas / Receptores Androgênicos / Regulação Neoplásica da Expressão Gênica / Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: Cancer Cell Assunto da revista: NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos