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TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis.
Malek, Reem; Gajula, Rajendra P; Williams, Russell D; Nghiem, Belinda; Simons, Brian W; Nugent, Katriana; Wang, Hailun; Taparra, Kekoa; Lemtiri-Chlieh, Ghali; Yoon, Arum R; True, Lawrence; An, Steven S; DeWeese, Theodore L; Ross, Ashley E; Schaeffer, Edward M; Pienta, Kenneth J; Hurley, Paula J; Morrissey, Colm; Tran, Phuoc T.
Afiliación
  • Malek R; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Gajula RP; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Williams RD; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Nghiem B; Department of Urology, University of Washington, Seattle, Washington.
  • Simons BW; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Nugent K; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Wang H; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Taparra K; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Lemtiri-Chlieh G; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Yoon AR; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • True L; Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
  • An SS; Department of Pathology, University of Washington, Seattle, Washington.
  • DeWeese TL; Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
  • Ross AE; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Schaeffer EM; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland.
  • Pienta KJ; Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Hurley PJ; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Morrissey C; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Tran PT; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Res ; 77(12): 3181-3193, 2017 06 15.
Article en En | MEDLINE | ID: mdl-28484075
ABSTRACT
TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181-93. ©2017 AACR.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Proteínas Nucleares / N-Metiltransferasa de Histona-Lisina / Proteínas de Homeodominio / Proteína 1 Relacionada con Twist / ARN Largo no Codificante / Invasividad Neoplásica Límite: Animals / Humans / Male Idioma: En Revista: Cancer Res Año: 2017 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Proteínas Nucleares / N-Metiltransferasa de Histona-Lisina / Proteínas de Homeodominio / Proteína 1 Relacionada con Twist / ARN Largo no Codificante / Invasividad Neoplásica Límite: Animals / Humans / Male Idioma: En Revista: Cancer Res Año: 2017 Tipo del documento: Article