PI3K-regulated Glycine N-methyltransferase is required for the development of prostate cancer

Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Sonia Fernandez-Ruiz, Cristina Viera, Onintza Carlevaris, Amaia Ercilla, Isabel Mendizabal, Teresa Martin, Alice Macchia, Laura Camacho, Mikel Pujana-Vaquerizo, Pilar Sanchez-Mosquera, Verónica Torrano, Natalia Martin-Martin, Patricia Zuniga-Garcia, Mireia Castillo-Martin, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Miguel Unda, Jose M. MatoEdurne Berra, Maria L. Martinez-Chantar, Arkaitz Carracedo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Glycine N-Methyltransferase (GNMT) is a metabolic enzyme that integrates metabolism and epigenetic regulation. The product of GNMT, sarcosine, has been proposed as a prostate cancer biomarker. This enzyme is predominantly expressed in the liver, brain, pancreas, and prostate tissue, where it exhibits distinct regulation. Whereas genetic alterations in GNMT have been associated to prostate cancer risk, its causal contribution to the development of this disease is limited to cell line-based studies and correlative human analyses. Here we integrate human studies, genetic mouse modeling, and cellular systems to characterize the regulation and function of GNMT in prostate cancer. We report that this enzyme is repressed upon activation of the oncogenic Phosphoinositide-3-kinase (PI3K) pathway, which adds complexity to its reported dependency on androgen signaling. Importantly, we demonstrate that expression of GNMT is required for the onset of invasive prostate cancer in a genetic mouse model. Altogether, our results provide further support of the heavy oncogenic signal-dependent regulation of GNMT in prostate cancer.

Original languageEnglish
Article number10
JournalOncogenesis
Volume11
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

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