# Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $599,069

## Abstract

Intermediates generated in cell metabolism also serve as substrates for covalent
modification of chromatin, enabling the potential coupling of metabolic states and
epigenetic control. This interplay between metabolic control and epigenetic
reprogramming has been recently been proposed as a potential mechanism for
regulation of stem cell differentiation and for pathologic processes such as cancer. We
identify such a network as a major mediator of cell transformation downstream of the
LKB1, an important tumour suppressor that is mutationally inactivated in many cancers
(e.g. lung, pancreas). LKB1 encodes a serine-threonine kinase that integrates nutrient
availability, metabolism and growth, although the mechanisms for LKB1-dependent
tumour suppression remain elusive. By developing primary epithelial cell models and
employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic
cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding
in human cancer, is fueled by pronounced rewiring of nutrient utilization. In particular, we
demonstrate that LKB1 inactivation potentiates glycolysis while also channeling
glycolytic intermediates to the serine-glycine-one carbon network coupled to generation
of the methyl donor S-adenosylmethionine (SAM). In concert, DNA methyltransferases
(DNMT1 and DNMT3A) are upregulated, leading to global elevation in genomic 5-
methylcytosine levels. Correspondingly, LKB1 deficiency renders cells independent of
exogenous serine for growth, but highly sensitive to inhibition of serine biosynthesis and
DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting
from loss of LKB1 that links rewiring of glucose metabolism and chromatin regulation.
This state both potentiates and is critically required for the tumorigenic program of LKB1-
mutant cells, suggesting novel points of therapeutic intervention in defined patient
subsets. Here, we will build on these exciting findings, with the goals of defining how this
enhanced DNA methylation contributes to the tumor phenotypes, deciphering the
signaling and transcriptional pathways by which LKB1 loss activates to SGOC network,
and further establishing the therapeutic potential of targeting this pathway in relevant in
vivo preclinical models.

## Key facts

- **NIH application ID:** 10083201
- **Project number:** 5R01CA215498-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,069
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083201

## Citation

> US National Institutes of Health, RePORTER application 10083201, Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics (5R01CA215498-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083201. Licensed CC0.

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