# Epigenetic control of the metabolic tumor suppressor FBP1 in liver cancer

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $45,520

## Abstract

Abstract
Hepatocellular carcinoma (HCC) is the primary form of liver cancer and afflicts over half a million people
worldwide. Alarmingly, mortality rates have steadily increased in recent years, highlighting the importance of
identifying new therapies. One promising area of treating HCC is in targeting cellular metabolism. Specifically,
aerobic glycolysis is a common feature of liver cancer, which is an otherwise genetically and pathologically
heterogeneous disease. Neoplastic hepatocyte cells attain this glycolytic phenotype in part by decreasing
physiological gluconeogenesis. Indeed, the mRNA and protein levels of a rate-limiting gluconeogenic enzyme,
fructose-1,6-bisphosphatase 1 (FBP1), are significantly depleted in HCC. Our lab has found that ectopically
expressing FBP1 in HCC xenografts reduces tumor growth, whereas deleting Fbp1 accelerates autochthonous
models of liver cancer. These results suggest a strong tumor suppressive role for FBP1, and substantiate the
therapeutic potential of FBP1 activity. Therefore, my overall goal is to elucidate the mechanism of FBP1
repression to discover new therapeutic strategies for HCC. Three key pieces of preliminary data indicate
that the histone 3 lysine 27 (H3K27) methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), contributes to
FBP1 suppression: (1) publicly available ChIP-seq data reveals EZH2 enrichment sites at the FBP1 gene locus
in human embryonic stem cells. (2) EZH2 mRNA levels progressively increase with HCC stage and negatively
correlate with FBP1 expression. (3) Functionally, depleting EZH2 in HCC cells increases FBP1 mRNA,
whereas elevating EZH2 expression in normal hepatocytes diminishes FBP1 protein abundance. I
hypothesize that EZH2 directly catalyzes H3K27 trimethylation at the FBP1 promoter to suppress its
transcription, and inhibiting EZH2 will reduce HCC growth, in part, through metabolic consequences of
FBP1 activation. To address these ideas, I will first characterize the physical interaction of EZH2 with the
FBP1 locus in HCC by ChIP. Additionally, I will determine how EZH2 is recruited to the FBP1 promoter by
performing co-IP and mass spectrometry, followed by validation of candidate binding partners. Second, to
determine biological effects relevant to clinical response, I will perform comprehensive metabolite analyses of
HCC cells under conditions of EZH2 loss. Importantly, I expect to see both FBP1-dependent and independent
alterations in metabolism upon EZH2 reduction, which will have implications for metabolite biomarkers,
synthetic lethality, and resistance mechanisms. This work will decipher the complex nature of FBP1 epigenetic
silencing in HCC, and outline new treatment paradigms that reactivate gluconeogenesis in HCC.

## Key facts

- **NIH application ID:** 9959179
- **Project number:** 5F31CA239514-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jason Godfrey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959179

## Citation

> US National Institutes of Health, RePORTER application 9959179, Epigenetic control of the metabolic tumor suppressor FBP1 in liver cancer (5F31CA239514-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9959179. Licensed CC0.

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