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Reversible epigenetic alterations mediate PSMA expression heterogeneity in advanced metastatic prostate cancer.
Sayar, Erolcan; Patel, Radhika A; Coleman, Ilsa M; Roudier, Martine P; Zhang, Ailin; Mustafi, Pallabi; Low, Jin-Yih; Hanratty, Brian; Ang, Lisa S; Bhatia, Vipul; Adil, Mohamed; Bakbak, Hasim; Quigley, David A; Schweizer, Michael T; Hawley, Jessica E; Kollath, Lori; True, Lawrence D; Feng, Felix Y; Bander, Neil H; Corey, Eva; Lee, John K; Morrissey, Colm; Gulati, Roman; Nelson, Peter S; Haffner, Michael C.
Afiliação
  • Sayar E; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Patel RA; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Coleman IM; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Roudier MP; Department of Urology, University of Washington (UW), Seattle, Washington, USA.
  • Zhang A; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Mustafi P; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Low JY; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Hanratty B; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Ang LS; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Bhatia V; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Adil M; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Bakbak H; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Quigley DA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
  • Schweizer MT; Division of Medical Oncology, Department of Medicine, UW, Seattle, Washington, USA.
  • Hawley JE; Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Kollath L; Division of Medical Oncology, Department of Medicine, UW, Seattle, Washington, USA.
  • True LD; Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Feng FY; Department of Urology, University of Washington (UW), Seattle, Washington, USA.
  • Bander NH; Department of Laboratory Medicine and Pathology, UW, Seattle, Washington, USA.
  • Corey E; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
  • Lee JK; Department of Urology, Weill Cornell Medicine, New York, New York, USA.
  • Morrissey C; Department of Urology, University of Washington (UW), Seattle, Washington, USA.
  • Gulati R; Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  • Nelson PS; Department of Urology, Weill Cornell Medicine, New York, New York, USA.
  • Haffner MC; Department of Urology, University of Washington (UW), Seattle, Washington, USA.
JCI Insight ; 8(7)2023 04 10.
Article em En | MEDLINE | ID: mdl-36821396
Prostate-specific membrane antigen (PSMA) is an important cell surface target in prostate cancer. There are limited data on the heterogeneity of PSMA tissue expression in metastatic castration-resistant prostate cancer (mCRPC). Furthermore, the mechanisms regulating PSMA expression (encoded by the FOLH1 gene) are not well understood. Here, we demonstrate that PSMA expression is heterogeneous across different metastatic sites and molecular subtypes of mCRPC. In a rapid autopsy cohort in which multiple metastatic sites per patient were sampled, we found that 13 of 52 (25%) cases had no detectable PSMA and 23 of 52 (44%) cases showed heterogeneous PSMA expression across individual metastases, with 33 (63%) cases harboring at least 1 PSMA-negative site. PSMA-negative tumors displayed distinct transcriptional profiles with expression of druggable targets such as MUC1. Loss of PSMA was associated with epigenetic changes of the FOLH1 locus, including gain of CpG methylation and loss of histone 3 lysine 27 (H3K27) acetylation. Treatment with histone deacetylase (HDAC) inhibitors reversed this epigenetic repression and restored PSMA expression in vitro and in vivo. Collectively, these data provide insights into the expression patterns and regulation of PSMA in mCRPC and suggest that epigenetic therapies - in particular, HDAC inhibitors - can be used to augment PSMA levels.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: JCI Insight Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias de Próstata Resistentes à Castração Limite: Humans / Male Idioma: En Revista: JCI Insight Ano de publicação: 2023 Tipo de documento: Article