DNA methylation deregulation in murine cutaneous squamous cell
Background: Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies, with rising incidence rates. There are limited treatment options for advanced and metastatic cSCC and particularly high-risk groups, such as organ transplant recipients, are in urgent need for strategies to treat aggressive cSCC. We have previously developed a preclinical murine model for cSCC, with remarkably similar histopathology and genetics to human cSCC. Understanding the impact of DNA methylation in cSCC may provide avenues to develop new treatment or prevention strategies. Here, we perform reduced-representation bisulfite sequencing based DNA methylation analysis of a murine cSCC model (6 tumors, 6 controls, 2 independent healthy skin samples) and compare results with publicly available human cSCC methylation data for two cSCC subtypes, stem-cell like and keratinocyte like tumors. Results: Contrasting most cancers, general DNA hypermethylation was previously reported for high-risk human cSCC. Similarly, we found significantly increased average methylation in mouse cSCC as well as in stem-cell like, but not keratinocyte like, human cSCC. Locus specific methylation changes in mouse cSCC often occurred in regions of potential regulatory function, including enhancers and promoters. One differentially methylated region was located in a potential enhancer of the tumor suppressor gene Filip1l and expression of this gene was significantly reduced in mouse tumors and human cSCC cell lines. Furthermore, comparison of differentially methylated genes revealed remarkable similarities between human and mouse cSCC. Conclusion: Our data suggest that, in addition to mutations, deregulation of DNA methylation is an important feature of murine and human cSCC. DNA methylation likely contributes to silencing of tumor suppressor genes, as shown for the Filip1l gene. The similarities between mouse and human cSCC, particularly stem-cell like, highlight the clinical relevance of our model and presents unique opportunities to identify new treatment strategies. Overall design: We performed reduced-representation bisulfite sequencing based DNA methylation analysis of a murine cSCC model (6 tumors, 6 controls, 2 independent healthy skin samples) and compared results with publicly available human cSCC methylation data for two cSCC subtypes, stem-cell like and keratinocyte like tumors.