Abstract

Malignant melanoma is a type of very dangerous skin cancer. Histone modifiers usually become dysregulated during the process of carcinoma development, thus there is potential for a histone modifier inhibitor as a useful drug for cancer therapy. There is a multitude of evidence regarding the role of G9a, a histone methyltransferase (HMTase), in tumorigenesis. In this study, we first showed that G9a was significantly upregulated in melanoma patients. Using the TCGA database, we found a significantly higher expression of G9a in primary melanoma samples (n = 461) compared to normal skin samples (n = 551). Next, we knocked down G9a in human M14 and A375 melanoma cell lines in vitro via small interfering RNA (siRNA). This resulted in a significant decrease in cell viability, migration and invasion, and an increase in cell apoptosis. UNC0642 is a small molecule inhibitor of G9a that demonstrates minimal cell toxicity and good in vivo pharmacokinetic characteristics. We investigated the role of UNC0642 in melanoma cells, and detected its anti-cancer effects in vitro and in vivo. Next, we treated cells with UNC0642, and observed a significant decrease in cell viability in M14 and A375 cell lines. Furthermore, treatment with UNC0642 resulted in increased apoptosis. In immunocompetent mice bearing A375 engrafts, treatment with UNC0642 inhibited tumor growth. Results of Western blot analysis revealed that administration of UNC0642 or silencing of G9a expression by siRNA reduced Notch1 expression significantly and decreased the level of Hes1 in A375. All in all, the data from our study demonstrates potential of G9a as a therapeutic target in the treatment of melanoma.

Highlights

  • Malignant melanoma, which develops from pigmentcontaining cells called melanocytes [1, 2], is one of the most aggressive forms of skin cancer

  • All of the results indicated that G9a played a crucial role in maintaining melanoma proliferation

  • These results suggest that G9a promotes the migration and invasion of melanoma cell lines

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Summary

Introduction

Malignant melanoma, which develops from pigmentcontaining cells called melanocytes [1, 2], is one of the most aggressive forms of skin cancer. Melanomas are most commonly located in the skin, but can occur in the mouth, intestines, or eyes. As the the most dangerous type of skin cancer [3], there were approximately 232,000 new occurrences of melanoma in 2012 across the world. Melanoma most commonly develops when people with low skin pigmentation levels are exposed to ultraviolet light. Wearing sunscreen and avoiding ultraviolet rays can contribute to the prevention of melanoma [4]. Utilization of immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival, but resistance to conventional chemotherapy and radiotherapy is common. In the United States, there is a 98% five-year www.aging-us.com survival rate among patients with a localized tumor, but only a 16% five-year survival rate once the melanoma has spread [6]

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