Exploring anti-sense RNAs in melanocyte transformation and melanoma formation

SUMMARY In the last decade, noncoding RNAs (ncRNAs) have emerged as key regulators of various biological processes, potentially impacting the development of diseases, including cancer. One class of ncRNAs, known as antisense RNAs (asRNAs) are transcribed in the opposite orientation to and overlap with genes encoding protein-coding mRNAs. Human cells harbor numerous asRNA, and we have discovered several that exhibit differential expression during melanoma development. However, the molecular mechanisms underlying the functions of asRNA, whether they regulate the overlapping sense transcript in cis or other genes in trans, are poorly understood. Additionally, the contribution of asRNAs to melanomagenesis remains unknown, partly due to the lack of a versatile genetic toolbox for modulating endogenous asRNA transcription and abundance. To address this gap, we have developed genetic tools that enable stable modulation of candidate asRNA transcription and abundance, which we will implement in this R21 proposal. Using these innovative tools, we aim to assess the tumor suppressive potential of a specific asRNA that we hypothesize to suppress melanomagenesis. Through comprehensive analysis of asRNA expression in benign melanocytes and malignant melanoma cells, we have identified CDH3-AS1 as a promising candidate melanoma suppressor. Our study will investigate whether deregulation of CDH3-AS1 promotes melanocyte transformation and melanoma malignancy in vitro and tumor formation in xenograft models. Furthermore, we will delve into the molecular characterization of CDH3-AS1’s tumor suppressor activity, with a particular focus on its regulation of the overlapping sense gene, CDH3, which encodes the putative melanoma suppressor P-Cadherin. Through our proposed studies, we aim to demonstrate the pivotal role of decreased CDH3-AS1 expression in driving melanomagenesis. Moreover, our experimental framework will establish a flexible foundation for future investigations of asRNA associated with melanoma. By shedding light on the functions and implications of melanoma-associated asRNAs, our research will contribute to advancing the understanding and potential treatment of this complex disease. Project Number: 1R21CA303007-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Florian Karreth | Institution: H. LEE MOFFITT CANCER CTR & RES INST, TAMPA, FL | Award Amount: $433,256 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZCA1 RTRB-S (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11210445