Cutaneous SCC (cSCC) is the second most frequent type of human malignancy worldwide primarily caused by chronic long-term sun exposure. Somatic mutations in the tumor suppressor gene TP53 have been shown to occur frequently in aged sun-exposed skin and to favor clonal expansion. In contrast, p63, a p53 family member, is rarely mutated in cancer and rather is overexpressed and/or amplified in squamous cell carcinomas. Several studies have shown that p63 overexpression leads to higher proliferation rates and an increased ability to contrast differentiation, cellular senescence and apoptosis. One of the most possible therapeutic approach for cancer is to alter the transcriptional dysregulation by perturbation of the epigenetic modification. Using a proteomic screening, we identified PARP1 as a p63 protein partner. PARP1 is an enzyme that add PAR moieties onto target proteins and regulates different cellular processes including DNA repair and transcriptional regulation. Furthermore, it is a new therapeutic target for several tumor such as breast cancer and ovarian cancer. Similar to p63, PARP1 is highly induced in a large cohort of cSCC samples and in cSCC cell lines. To investigate whether PARP1 and p63 coordinately regulate global patterns of gene expression, either PARP1 or p63 were knocked down in SCC cells followed by RNA-seq. Correlation analyses of the transcriptomic profile under basal condition, showed that the majority of genes affected by the depletion of one factor were similarly affected by the depletion of the other, causing a highly significant coordinated perturbation in transcription. Furthermore, most of the downregulated genes in PARP1 and p63 depleted cells are involved specifically in cell cycle progression and mitosis. Taken together these data reveal a previously unrecognized functional interaction between p63 and PARP1 in regulating transcription of a large set of cell cycle genes during early stages of skin tumorigenesis, potentially opening a window for novel therapeutic intervention.

Overlapping functions of PARP1 and p63 in cutaneous squamous cell carcinoma