# Identification of USP13 as a therapeutic target for ovarian cancer

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $357,498

## Abstract

Project Summary
 The Cancer Genome Atlas has uncovered mutations in human ovarian cancer (OVCA) genomes
that potentially drive tumorigenesis and alter cell metabolism to meet the crucial requirements of tumor
cells. Whereas mutations in metabolic enzymes hardwire metabolism to tumorigenesis, they are relatively
infrequent in OVCA. More often, cancer metabolism is altered by the abundance and activity of the metabolic
enzymes through ubiquitin-proteasome proteolysis. We applied bioinformatic tools and meta-analysis to
analyze genes in the ubiquitin-proteasome proteolysis and determined their molecular interactions with cell
metabolism. The most significantly modulated gene identified from our analyses is ubiquitin specific
peptidase 13 (USP13). The proposed studies are based on the three novel findings: 1) In-depth analysis
of OVCA genomes identified copy number gains of USP13 gene in 29.3% (158 out of 538) of high- grade
serous OVCA, but only in 3.7% of breast cancer and in 0% of colorectal cancer, suggesting that USP13
amplification is a unique and frequent genomic event in OVCA; 2) Two potential deubiquitination targets
of USP13, ATP citrate lyase (ACLY) and oxoglutarate dehydrogenase (OGDH), are key regulators that
determine glutaminolysis, tricarboxylic acid (TCA) cycle and lipid synthesis; 3) Metabolism of reactive
stromal cells in tumor microenvironment (TME) is reprogrammed through an elevated glutamine anabolic
pathway, which confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them
to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived
conditions in ovarian TME.
 Despite the fact that many ovarian tumors show increased uptake of glucose and glutamine and
elevated lipid metabolism, no molecular mechanisms have been identified and little progress has been made
towards harnessing the potential therapeutic use of these observations. The bottleneck is to find key
genomic alterations that drives OVCA cell metabolism. Here, we propose that 1) USP13 amplification drives
ovarian cancer cell metabolism by upregulating ACLY and OGDH, and 2) A synthetic lethal approach to
target PIK3CA and USP13 in in OVCA harboring the USP13 amplicon for desirable therapeutic outcomes.
We will test these hypotheses in three aims: Aim 1: To determine the USP13 induced metabolic
alterations in OVCA with USP13 amplification; Aim 2: To determine molecular mechanisms for the
regulation of USP13 activity; Aim 3: To assess the effects of USP13 inhibition in vivo using human ovarian
tumor models.
 The ability of USP13 in rewiring metabolism and its druggability fuel the interest in targeting USP13 and
cancer metabolism in OVCA, leading to the development of new therapeutics.

## Key facts

- **NIH application ID:** 10092972
- **Project number:** 5R01CA222251-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Xiongbin Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,498
- **Award type:** 5
- **Project period:** 2018-02-02 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092972

## Citation

> US National Institutes of Health, RePORTER application 10092972, Identification of USP13 as a therapeutic target for ovarian cancer (5R01CA222251-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092972. Licensed CC0.

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