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

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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 tumor development. Identification of Twist1 as a key early player in skin cancer development could lead to novel approaches for the prevention and treatment of cSCC. Development of novel agents for prevention and/or treatment as proposed in this grant application could lead to rapid translation of such agents into the clinic.