Regulation of Histone Deacetylases and long noncoding RNAs in malignant melanoma and their functional relevance in mediating resistance mechanisms induced by BRAF inhibitor treatment

• Applicant: Dr. Anja Heinemann
• Subject Area: Dermatology
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242751778

Malignant melanoma is the most serious type of skin cancer characterized by a high metastatic potential and continuously rising incidence rates. An efficient therapy of melanoma, especially of a subpopulation of melanoma cells carrying a BRAF mutation, is represented by the administration of the specific BRAF inhibitor PLX4032. Treatment with this inhibitor against the mutated V600E form of BRAF has shown clinical responses in a high proportion of patients with metastatic malignant melanoma. However, after initial responses of PLX4032 treatment, cells from these patients acquire resistance to the drug. One possibility to overcome the PLX4032 induced resistance is the simultaneous administration of the BRAF inhibitor PLX4032 together with Histone Deacetylase inhibitors (HDACs).Histone Deacetylases are chromatin-modifying enzymes that control gene expression by modifying histone residues which in turn remodels chromatin structure. HDACs are described to play a key role in suppressing apoptosis. They are highly expressed in melanoma cell lines that became resistant to a prolonged exposure of selective BRAF inhibitors pointing to an involvement of HDACs in mediating resistance to the inhibitors. Consequently, a treatment of HDAC inhibitors reverses the resistance of melanoma cells to induction of apoptosis by selective BRAF inhibitors. This project aims to elucidate the molecular mechanisms that regulate HDAC expression in malignant melanoma and their functional role in mediating resistance mechanisms induced by BRAF inhibitor treatment. Besides HDACs also long noncoding RNAs (lncRNAs) are highly expressed in malignant melanoma and have the capability to suppress apoptosis. It has been shown that an overexpression of lncRNAs protected melanoma cells from apoptosis. Thus the following project aims to elucidate whether lncRNAs are also involved in BRAF inhibitor induced resistance mechanisms.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Dr. Peter Hersey