# Project 2 - Protein Ubiquitylation in Esophageal Cancer

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $477,730

## Abstract

PROJECT SUMMARY – PROJECT 2
Cyclin D1 deregulation is observed frequently observed in human cancers especially in esophageal squamous
cell carcinoma (ESCC) and esophageal adenocarcinomas (EAC). This deregulation implies that the cyclin
D1/CDK4 kinase provides cells with a growth advantage, thereby contributing to cancer development. We
have demonstrated that loss of Fbxo4, a component of the E3 ligase, SCFFBXO4, occurs in ESCC and FBXO4
knockout mice are susceptible to tumors. Additional work has revealed that FBXO4 regulates degradation of
two distinct oncogenes in ESCC: cyclin D1 and FXR1. Overexpression of cyclin D1 increases mitogen-
independent cell proliferation and FXR1 overexpression contributes to bypass of cell senescence and
collective tumor initiation. In our new preliminary data, we have discovered that loss of FBXO4 results in cell
addiction to Glutamine. In this context, glutamine appears essential due to its metabolic role, wherein it is
metabolized to α-ketoglutarate, an intermediate in the TCA cycle. Cells with mutant FBXO4 quickly undergo
apoptosis under conditions of glutamine restriction. Given the generation of inhibitors of glutaminase, this
observation provides a potential novel strategy for therapeutic intervention. These exciting discoveries provide
critical insights into the mechanisms whereby FBXO4 suppresses neoplastic growth and support the notion
that targets of FBXO4 such as FXR1 and cyclin D1/CDK4 activity are key esophageal cancer drivers. The
identification of the SCFFBX4 as the cyclin D1 E3 ligase as well as our preliminary studies lead to the
overarching hypothesis that the SCFFBX4 E3 ligase maintains threshold levels of the cyclin D1/CDK4 kinase
and the FXR1, an RNA binding protein, to maintain esophageal tissue homeostasis. We hypothesize further
that cyclin D1 and FXR1 overexpression foster ESCC progression, resulting in cellular vulnerabilities that can
be rationally targeted. This hypothesis will be pursued through the following interrelated Specific Aims: (1)
To determine the contribution of deregulated cyclin D1 to mutant FBXO4 driven glutamine-dependence in
esophageal cancer; (2) To determine the mechanism(s) whereby mutant p53R172H cooperates with cyclin
D1T286A to drive ESCC pathogenesis; and (3) To determine the therapeutic potential of targeting glutamine-
metabolism in ESCC with dysregulated cyclin D/CDK4. Our collaborative work with Projects 1 and 2, along
with support from the Core Facilities, provides new basic and translational perspectives on the cyclin
D1/CDK4/CDK6 axis and glutamine metabolism in ESCC.

## Key facts

- **NIH application ID:** 10214545
- **Project number:** 5P01CA098101-19
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** John Alan Diehl
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $477,730
- **Award type:** 5
- **Project period:** 2003-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214545

## Citation

> US National Institutes of Health, RePORTER application 10214545, Project 2 - Protein Ubiquitylation in Esophageal Cancer (5P01CA098101-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214545. Licensed CC0.

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