Project Funding Details

Head and Neck Squamous Cell Carcinoma (HNSCC), one of the most common types of cancer, shows a very poor outcome in advanced stages, as, indeed, current therapeutic strategies struggle in tackling aggressive disease. HNSCC is characterised by specific genetic and epigenetic alterations leading to a dysregulation of pathways and resulting in enhanced proliferation, increased migration, and immune escape. In the previous Grant IG2019 we identified ZNF148, a novel binding partner for the oncogene p63. ZNF148 is often overexpressed in cancer and our preliminary data suggest that ZNF148 establishes distinct routes of transcription regulation, both p63-dependent and independent, to acquire control over cell growth and immune response. Nonetheless, precise molecular mechanisms underlying p63/ZNF148 axis in HNSCC remain elusive. Based on our preliminary data, we hypothesize an essential pro-tumour role for p63/ZNF148 axis and ZNF148 alone in HNSCC progression via (1) epigenetic control of proliferation; (2) regulation of interferon signalling. To test our hypotheses, we will set two major work packages: (WP1) an in-depth characterisation of p63/ZNF148 role in boosting tumour growth and investigation of its clinical relevance; (WP2) a comprehensive exploration of ZNF148 binding landscape on chromatin, its targetome and interactome in HNSCC in normal conditions and subjected to stimulation with cytokines. We will employ a plethora of molecular biology and biochemical techniques both in vitro and in vivo. We will perform transcriptomics coupled with genome-wide occupancy profiling to study transcriptional programs of p63 and ZNF148 transcription factor. Phenotypic analyses, molecular biology techniques such as ChIP, co-IP, and fractionation will enable a comprehensive dissection of identified pathways at molecular level. The importance of uncovered routes for p63 and ZNF148 activity will be studied both in animal models and human HNSCC samples. We expect to characterise epigenetic regulation of p63/ZNF148 target CCND1 and propose its clinical relevance. We proposed epigenome editing to reduce CCND1 expression, as innovative approach. Moreover, further analyses of ZNF148 targetome will identify novel target genes and their involvement in HNSCC progression. Therefore, the results produced in this project will provide a comprehensive overview of distinct transcriptional programs orchestrated by oncogenes p63, ZNF148 and their targets which guide cancer progression. This project will uncover novel molecular pathways with a translational potential. Understanding of molecular mechanisms of proliferation and immune escape regulated by oncogenes p63 and its co-binding partner ZNF148, will lead to identification of novel key players determining HNSCC course and therapy efficacy. In addition, we proposed epigenome editing to reduce CCND1 expression, as innovative approach. Importantly, we will identify new markers defining outcomes of existing therapeutic strategies, allowing a step forward towards precision medicine. The innovation of this proposal lies in the originality and implications of the questions addressed; in the long term, these questions might provide innovative therapeutic approaches to cancer treatment. The novelty of our hypotheses defines the high risk of this project, which is reduced by solid preliminary data that support the rationale of our tasks and, therefore, ensures the success of the project.