# Targeting Super-Enhancers Suppresses Cancer Stemness and Invasion of HNSCC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $397,538

## Abstract

The long-term objectives of this application are to understand how super-enhancers (SEs) control the
invasive growth and metastasis of head and neck squamous cell carcinoma (HNSCC) and to develop novel
therapeutics for HNSCC. HNSCC is highly invasive and resistant to cancer therapy and frequently metastasizes
to cervical lymph node, and patients with HNSCC have poor prognosis compared to other cancers such as
breast and colorectal cancers. Therefore, novel effective therapies need to be developed for HNSCC patients.
SEs are a genomic region that consists of multiple enhancers which are collectively bound by a set of
transcription factors and epigenetic readers to drive transcription of genes associated with cell identity.
Bromodomain-containing protein 4 (BRD4) is one of the four bromodomain and extra-terminal motif (BET)
protein family members. In SEs, BRD4 functions as an epigenetic reader that recognizes and interacts with
acetylated lysine residues on histone H3 and H4. Upon binding to the acetylated histones, BRD4 recruits the
Mediator complex, the cyclin-dependent kinase 7 (CDK7) complex, and other factors to facilitate transcription
initiation and elongation. Growing evidence suggests that SEs preferentially regulated the transcription of key
oncogenes in various cancers which can be selectively inhibited by BET inhibitors (BETi). To explore whether
SEs are a therapeutic target for HNSCC, we performed preliminary studies to characterize SEs in HNSCC, and
discovered that SEs selectively controlled the transcription of a set of oncogenic genes associated with cancer
stemness and invasion in addition to some common tumor-promoting genes. Using the newly-established
mouse model of HNSCC that allows us to trace cancer stem cells (CSCs) in vivo, we found that disruption of SEs
by BETi could potently eliminate CSCs and inhibit HNSCC invasive growth in vivo. We also showed that the new
BET degrader (BETd) potently inhibited the expression of cancer stemness and pro-invasive genes by inducing
BET family protein degradation. Based on these exciting preliminary studies, in this application, we hypothesize
that SEs control the expression of cancer stemness and pro-invasive genes, and targeting SEs by BETd might
help to eliminate CSCs and block tumor cell invasion, thereby improving anti-tumor efficacy and preventing
lymph node metastasis of HNSCC. To test our hypothesis, we propose the following three specific aims: 1)
Determine whether disruption of SEs suppresses tumor invasive growth and metastasis and effectively
eliminates CSCs in a mouse model of HNSCC; 2) Determine whether the disruption of SEs inhibits the
self-renewal, tumorigenic potentials and metastasis of CSCs isolated from human HNSCC; and 3) Determine
how SEs are assembled in HNSCC and explore the molecular mechanisms by which disruption of SEs inhibits
cancer stemness and invasion of HNSCC. Novel findings from our studies may lead to the development of novel
strategies for the treatmen...

## Key facts

- **NIH application ID:** 10224169
- **Project number:** 5R01DE029173-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** CUN-YU WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,538
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224169

## Citation

> US National Institutes of Health, RePORTER application 10224169, Targeting Super-Enhancers Suppresses Cancer Stemness and Invasion of HNSCC (5R01DE029173-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224169. Licensed CC0.

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