NNMT Loss Drives Cancer Progression by enhancing SAM availability for mTORC1 Signaling and Chromatin Methylation

Area of Science:

• Cancer Biology
• Epigenetics
• Metabolic Regulation

Background:

• Aberrant epigenetic reprogramming and dysregulated mTOR signaling are cancer hallmarks.
• S-adenosylmethionine (SAM) is crucial for cancer progression, but its sustained availability is poorly understood.
• Nicotinamide N-methyltransferase (NNMT) is identified as a key regulator.

Purpose of the Study:

• To investigate the role of NNMT in prostate cancer (PCa) progression.
• To elucidate the mechanisms by which NNMT loss impacts cancer metabolism and signaling.
• To identify potential therapeutic strategies for NNMT-deficient PCa.

Main Methods:

• Utilized a prostate-specific *Nnmt* knockout mouse model.
• Analyzed human PCa samples for NNMT genomic deletions and protein expression.
• Assessed intracellular SAM levels, mTORC1 signaling, and chromatin methylation.
• Investigated the effects of dietary methionine restriction (MR) and mTORC1 inhibition.

Main Results:

• NNMT loss accelerates PCa progression, especially with *Pten* deletion, leading to reduced survival.
• NNMT loss increases intracellular SAM, activating mTORC1 signaling and enhancing chromatin methylation.
• Human PCa frequently shows NNMT deletions and absent protein expression.
• NNMT-deficient PCa cells exhibit heightened mTORC1 activity and sustained growth under MR.
• Combined MR and mTORC1 inhibition synergistically suppress NNMT-deficient tumor growth.

Conclusions:

• NNMT is a critical tumor suppressor that limits SAM-driven epigenetic and signaling pathways in PCa.
• NNMT loss creates a therapeutic vulnerability exploitable by combined MR and mTORC1 inhibition.
• This study suggests a rational, diet-based therapeutic approach for advanced cancers with NNMT loss.