# DDB2 is a regulator of HIF1A and EMT in HNSCC

> **NIH NIH R03** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $79,950

## Abstract

Abstract/Summary
Rationale: HNSCC are particularly aggressive due to high incidence of recurrence and distant metastasis.
Majority of HNSCC are detected and treated at stage III/IV. For this reason, despite significant advances in
surgery, radiation therapy and chemotherapy, the 5-year/50% survival rate of HNSCC has not improved
significantly over the past 35 years. The minority and medically underserved populations lack early detection,
which contribute to a high death rate. A clearer understanding of the molecular mechanisms underlying
aggressive progression of HNSCC is critical for early detection and development of effective therapeutic
intervention against this deadly disease.
This proposal focuses on the regulation of Hypoxia-signaling by DDB2 in HNSCC. DDB2 (XPE) is a sensor of
DNA damage and it plays an important role in Global Genomic Repair (GG-NER). Interestingly, loss of DDB2
expression in HNSCC coincides with metastatic progression and reduced survival. Our recent studies show that
DDB2 blocks mRNA expression of HIF1α and key HIF1α-target genes in HNSCC cells. HIF1α mediates key
transcriptional responses to hypoxia. Specifically, high HIF1α in tumors is associated with a more aggressive
tumor phenotype and worse survival in HNSCC and a 15-gene hypoxia profile has demonstrated to have
prognostic significance in HNSCC. We also observed that DDB2 constitutively represses the EMT regulators
Snail and Zeb1 and EMT markers, Vimentin, E-Cad and N-Cad in SCC9 and SCC15 HNSCC cells. While recent
meta-analysis of gene expression data from HNSCC characterized the hypoxia-type and the mesenchymal type
(EMT-type) as two most aggressive cancer clusters, the mechanism of de-regulation is poorly understood. Our
hypothesis is that DDB2 plays a major defensive role against hypoxia-related pro-metastatic changes in HNSCC.
The loss of DDB2 observed in high-grade/metastatic HNSCC brings about high-levels of HIF1α-activity, and
expression of the HIF1α-target genes that are normally activated during hypoxia. The proposed studies will allow
us to describe a new arm of hypoxia signaling in HNSCC.
The Specific Aims are to
(1) Investigate whether DDB2 opposes hypoxia response in HNSCC cells
(2) Investigate the expression patterns of DDB2 and HIF1α in HNSCC TumorMicroarrays
(3) Investigate whether loss of DDB2 drives aggressive Oral tumors in mice
These studies will have exciting implications about identification of reduced level of DDB2 as a potential
biomarker for progression of HNSCC, as well as towards therapy of aggressive cancers because DDB2
expression can be stimulated by PEITC.

## Key facts

- **NIH application ID:** 9832668
- **Project number:** 5R03CA227308-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SRILATA BAGCHI
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,950
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832668

## Citation

> US National Institutes of Health, RePORTER application 9832668, DDB2 is a regulator of HIF1A and EMT in HNSCC (5R03CA227308-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9832668. Licensed CC0.

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