[R01] The Role of NNMT in Prostate Cancer
Ente: National Cancer Institute
Scadenza: 2031-06-30
Importo max: 467.406 EUR
Paese: US
Descrizione
Project Summary: Every year, approximately 250,000 men in the United States are
diagnosed with prostate cancer (PCa), making it a significant cause of cancer-related
deaths, with over 30,000 annual fatalities. Elevated levels of epigenetic marks, such as
histone and DNA methylation, are linked to PCa progression and poor prognosis. Sadenosylmethionine
(SAM) plays a crucial role as the only methyl donor for all methylation
reactions in the cell including DNA and histone methylation reactions. Despite increased
SAM levels observed in advanced PCa, the mechanism behind the increased availability of
SAM in tumors cells and the development of a hypermethylated epigenome remains
unclear. A comprehensive insight into this process will lead to a better understating of PCa
etiology and innovative treatment strategies. In preliminary findings, we have identified
recurrent genetic deletion and potential chromatin looping-mediated transcriptional
silencing of NNMT in PCa. NNMT (Nicotinamide N-methyltransferase) is an enzyme
involved in methylation of nicotinamide to produce S-adenosylhomocysteine (SAH) and
1methylnicotinamide (MNAM), consuming SAM excessively (“SAM sink”) and thereby
reducing the overall methylation potential of the cell. We observed NNMT and androgen
receptor (AR) expression to be mutually exclusive in clinical datasets and PCa cell lines.
NNMT overexpression in human PCa cells and prostate-specific deletion in mice
(Genetically engineered mouse model -GEMM) showed reciprocal changes in SAM/SAH
ratio, global DNA methylation, and altered chromatin marks, impacting tumor growth in
vivo. Additionally, NNMT mediated SAM-sinking affected mTOR signaling promoting growth
in multiple PCa models. In this proposal, we aim to study tumor-suppressor role of NNMT
in PCa. We hypothesize that tumor-specific loss of NNMT leads to excess SAM availability,
driving DNA/chromatin methylation and mTOR activation, promoting PCa growth and
progression.
Vertebrate animal models are essential for this project because they provide the
physiological context necessary to investigate how NNMT loss influences prostate tumor
initiation, progression, epigenetic reprogramming, and therapeutic response in vivo.
Genetically engineered mouse models and xenograft studies will allow us to evaluate
tumor-host interactions and disease phenotypes that cannot be adequately recapitulated
in cell culture systems.
This hypothesis will be investigated through the following three major aims. Specific Aim 1:
Elucidate the mechanisms underlying NNMT silencing and its impact on the epigenome.
Specific Aim 2: Interrogate the impact of NNMT inactivation on PCa progression. Specific
Aim 3: Targeting the vulnerabilities in NNMT-deficient PCa.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Irfan Ahmed Asangani
Progetto: 1R01CA315904-01
Settori: National Cancer Institute
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