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Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A.
Whitlock, Nichelle C; White, Margaret E; Capaldo, Brian J; Ku, Anson T; Agarwal, Supreet; Fang, Lei; Wilkinson, Scott; Trostel, Shana Y; Shi, Zhen-Dan; Basuli, Falguni; Wong, Karen; Jagoda, Elaine M; Kelly, Kathleen; Choyke, Peter L; Sowalsky, Adam G.
Afiliação
  • Whitlock NC; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • White ME; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Capaldo BJ; Molecular Imaging Branch, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Ku AT; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Agarwal S; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Fang L; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Wilkinson S; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Trostel SY; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Shi ZD; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Basuli F; Chemistry and Synthesis Center, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Wong K; Chemistry and Synthesis Center, National Heart, Lung and Blood Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Jagoda EM; Molecular Imaging Branch, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Kelly K; Molecular Imaging Branch, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
  • Choyke PL; Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
  • Sowalsky AG; Molecular Imaging Branch, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
Discov Oncol ; 13(1): 97, 2022 Oct 01.
Article em En | MEDLINE | ID: mdl-36181613
ABSTRACT

BACKGROUND:

The activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.

RESULTS:

Using ChIP-seq against MYC, HOXB13, and AR in LNCaP cells, we observed redistribution of co-bound sites suggestive of differential KMT2A activity as a function of MYC expression. In a cohort of 177 laser-capture microdissected foci of prostate tumors, KMT2A expression was positively correlated with MYC activity, AR activity, and HOXB13 expression, but decreased with tumor grade severity. However, KMT2A expression was negatively correlated with these factors in 25 LuCaP patient-derived xenograft models of advanced prostate cancer and 99 laser-capture microdissected foci of metastatic castration-resistant prostate cancer. Stratified by KMT2A expression, ChIP-seq against AR and HOXB13 in 15 LuCaP patient-derived xenografts showed an inverse association with sites involving genes implicated in lipid metabolism, including the arachidonic acid metabolic enzyme PLA2G4F. LuCaP patient-derived xenograft models grown as organoids recapitulated the inverse association between KMT2A expression and fluorine-18 labeled arachidonic acid uptake in vitro.

CONCLUSIONS:

Our study demonstrates that the epigenetic activity of transcription factor oncogenes exhibits a shift during prostate cancer progression with distinctive phenotypic effects on metabolism. These epigenetically driven changes in lipid metabolism may serve as novel targets for the development of novel imaging agents and therapeutics.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Discov Oncol Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Discov Oncol Ano de publicação: 2022 Tipo de documento: Article