LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Area of Science:

• Oncology
• Metabolic pathways
• Epigenetics

Background:

• Intermediary metabolism provides substrates for chromatin modification, linking metabolic and epigenetic states.
• The liver kinase B1 (LKB1/STK11) tumor suppressor integrates nutrient availability, metabolism, and growth.
• LKB1 loss is implicated in oncogenic transformation.

Purpose of the Study:

• To identify the network linking metabolic and epigenetic alterations in LKB1-deficient cancers.
• To investigate the role of the serine-glycine-one-carbon pathway and S-adenosylmethionine in LKB1-mutant tumorigenesis.
• To explore therapeutic vulnerabilities associated with this metabolic-epigenetic reprogramming.

Main Methods:

• Genetically engineered mouse models and primary pancreatic epithelial cells.
• Transcriptional, proteomics, and metabolic analyses.
• Investigation of DNA methyltransferases and retrotransposon methylation.

Main Results:

• LKB1 loss coupled with KRAS activation induces an mTOR-dependent serine-glycine-one-carbon pathway, increasing S-adenosylmethionine.
• Upregulation of DNA methyltransferases leads to increased DNA methylation, particularly at retrotransposons.
• LKB1-deficient cells and tumors show sensitivity to inhibition of serine biosynthesis and DNA methylation.

Conclusions:

• A hypermetabolic state driven by LKB1 loss alters the epigenetic landscape to promote tumorigenesis.
• This metabolic-epigenetic reprogramming creates therapeutic vulnerabilities in LKB1-mutant cancers.
• Targeting serine biosynthesis or DNA methylation may be effective therapeutic strategies.