# Twist1 as a Target for Prevention and Treatment of Cutaneous Squamous Cell Carcinoma

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $344,441

## Abstract

PROJECT SUMMARY
The overall goal of the proposed research is to understand the role of Twist1 in cutaneous squamous cell
carcinoma (cSCC) and to develop novel approaches for targeting Twist1 for prevention and treatment of this
important disease. Twist1 is a transcription factor involved in epithelial-mesenchymal transition and cancer
progression and metastasis in a number of epithelial cancers. In previous studies from our laboratory, we found
that Twist1 was required for proliferation of keratinocytes during the process of skin tumor promotion by TPA
suggesting a role early in the process of skin carcinogenesis in addition to its role in cancer progression and
metastasis. These earlier studies showed that Twist1 regulated levels of G1-S-phase cell cycle proteins.
Furthermore, Twist1 was shown to regulate the function of p53 and p21. To date, the impact of Twist1 on UV
skin carcinogenesis has not been studied and therefore it is important to demonstrate that Twist1 also plays
critical role in UV skin carcinogenesis. In new preliminary experiments, we have found that deletion of Twist1 in
keratinocytes leads to keratinocyte differentiation. Furthermore, deletion of Twist1 in basal keratinocytes of
mouse epidermis in vivo leads to changes in bulge-region keratinocyte stem cells (KSCs), including migration of
KSCs out of the bulge region. These findings suggest that Twist1 may play an important role in regulating
keratinocyte differentiation and be required for KSC homeostasis. In additional preliminary experiments, we have
found that Ovol1 expression is significantly upregulated in Twist1 deficient keratinocytes and may be responsible
for driving differentiation. Furthermore, we have also found that Harmine, a naturally occurring compound
reported to inhibit Twist1 by facilitating its degradation, induces differentiation in keratinocytes and upregulates
Ovol1 in a manner similar to that seen in epidermis of Twist1 KO mice. In this proposal, we will test the
hypothesis that Twist1 plays a critical role in UV-induced cSCC by maintaining the balance between
proliferation and differentiation of epidermal keratinocytes, including KSCs via regulation of the levels of
Ovol1 and that targeting Twist1 will effectively inhibit UV-induced cSCC. The specific aims are as follows: i)
To further examine the role of Twist1 in regulating proliferation and differentiation of keratinocytes and KSCs; ii)
To examine the impact of keratinocyte specific deletion of Twist1 on UV-induced skin carcinogenesis; iii)
Determine the role of Ovol1 as a downstream effector of Twist1 in regulating proliferation and differentiation of
keratinocytes and KSCsand iv) Further evaluate the ability of Harmine, a novel Twist1 inhibitor, to prevent UV-
induced skin carcinogenesis. Completion of the proposed studies will further elucidate the role of Twist1 in
keratinocyte and KSC proliferation and differentiation and its role in development of cSCC, especially in the early
stages of skin t...

## Key facts

- **NIH application ID:** 10876471
- **Project number:** 5R01CA263535-04
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** John DiGiovanni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $344,441
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876471

## Citation

> US National Institutes of Health, RePORTER application 10876471, Twist1 as a Target for Prevention and Treatment of Cutaneous Squamous Cell Carcinoma (5R01CA263535-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10876471. Licensed CC0.

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