Specially Appointed Professor Akira Kikuchi, Center for Infectious Diseases Education and Research, Osaka University, and Assistant Professor Koei Shinzawa, Graduate School of Medicine, Osaka University, have identified a novel cancer signaling axis and molecular target for treatment in malignant melanoma.

Malignant melanoma is a type of skin cancer that originates from melanocytes or nevi, causing about 80% of skin cancer-related deaths. It occurs more frequently in the skin of Caucasian individuals exposed to ultraviolet radiation from sunlight, and somatic mutations in genes such as BRAF and NRAS have been observed. While some cases have shown significant response to BRAF inhibitors, as well as antibodies against CTLA-4 and PD-1 (immune checkpoint inhibitors), there are also cases in which these treatments have proven ineffective. Therefore, the development of new therapeutic agents for the cases resistant to these drug therapies has been required.

GREB1 is a nuclear protein that functions as a co-regulator for hormone receptors, enhancing their transcriptional activity. As it is induced by hormone receptors, it forms a positive feedback loop. GREB1 has been found to be upregulated in hormone-dependent cancers, including breast and prostate cancers, promoting the proliferation of these cancer cells. Although the association of GREB1 with hormone-independent cancers has been unclear so far, the research group had reported high expression of GREB1 in hepatoblastoma and hepatocellular carcinoma, promoting the proliferation of these cancer cells. In this study, the research group discovered that the expression of a specific isoform of GREB1 (Isoform 4, Is4) is induced in malignant melanoma cells under the influence of the melanocyte-specific transcription factor, MITF. They revealed that GREB1 Is4 promotes cancer cell proliferation through the regulation of pyrimidine metabolism. Furthermore, the anti-tumor effect of antisense nucleic acids against GREB1 showed a potential new modality for malignant melanoma.

In conclusion, these findings shed light on a promising molecular target for the treatment of malignant melanoma, potentially leading to the development of more effective therapies for cases that do not respond to current treatment options. This study was published in Oncogene on 1 September, 2023.

Melanoma is a malignant tumor caused by the cancerous transformation of melanocytes. The incidence of melanoma is high in Caucasians, but it affects 1 to 2 per 100,000 Japanese, and approximately 1,800 people are diagnosed with malignant melanoma per year in Japan. There are differences in response to immune checkpoint inhibitors by melanoma type, with low response rates in the acral and mucosal melanoma types, which are common among Japanese, while molecular targeted therapies (BRAF and MEK inhibitors) can prolong survival and achieve high response rates, but the incidence of drug resistance is a problem. About 30% of melanomas develop from pigmented nevi, and it has not been fully elucidated which genes are expressed in the neoplastic stage and how they become melanoma. The research group focused on the GREB1 Is4 gene, of which expression is induced by MITF, a pigment cell-specific transcription factor that produces pigments in melanocytes, to analyze its new role in cancer development and its potential as a new therapeutic target.

While immune checkpoint inhibitors have dramatically advanced the treatment of some cases of malignant melanoma, it is well known that other cases are still difficult to treat. The research group clarified a new mechanism of melanoma development mediated by GREB1 Is4 and demonstrated that it represents a potential new target for new melanoma therapy

Cancer cells are characterized by their repeated uncontrolled proliferation, and chemotherapy has traditionally been used to suppress cell proliferation by inhibiting the nucleic acids synthesis. In this study, the research group demonstrated that GREB1 Is4 stimulates the synthesis of its nucleic acid and melanomagenesis, promoting the proliferation of cancer cells.

Furthermore, the results of this study are of great social significance because GREB1 Is4 has been shown to be a therapeutic target in malignant melanoma, and antisense oligonucleic acids against GREB1 are expected to become new therapeutic agents in the future.

This research finding was published in Oncogene on 1 September, 2023.

Title:GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation

Authors:Koei Shinzawa*, Shinji Matsumoto, Ryota Sada, Akikazu Harada, Kaori Saitoh, Keiko Kato, Satsuki Ikeda, Akiyoshi Hirayama, Kazunori Yokoi, Atsushi Tanemura, Keisuke Nimura, Masahito Ikawa, and Tomoyoshi Soga, Akira Kikuchi*(*corresponding authors)

https://doi.org/10.1038/s41388-023-02803-6

This research was supported by Grants-in-Aid for Scientific Research (S, C) and the AMED-Project for Promotion of Cancer Research and Therapeutic Evolution and was conducted in collaboration with Departments of Genome Biology and Dermatology at Graduate School of Medicine at Osaka University, Research Institute for Microbial Diseases at Osaka University, and Institute for Advanced Biosciences at Keio University.