Suv-HMTases and their impact on tumor formation and telomere regulation

Epigenetic alterations during tumor formation and progression have become an increasingly important aspect of cancer biology. Loss of global methylation at histone H4 lysine 20, mediated by the Suv4-20 HMTases, and loss of methylation at histone H3 lysine 9 in Suv39 HMTase deficient mice were shown to promote tumor formation. A key function of Suv-HMTases is the generation and maintenance of constitutive heterochromatin at telomeres which plays a central role during tumorigenesis and stem cell activity. Transgenic mice were generated to address the role of Suv39h1 and Suv4-20h1 in tumorigenesis and telomere biology. Overexpression of Suv39h1 in pMEFs results in reduced transformation frequency and preliminary results suggest reduced papilloma formation during skin carcinogenesis. Suv39h1 overexpression in keratinocytes reduces the proliferative potential of skin stem cells in vitro. Suv39h1 overexpression in pMEFs leads to increased chromatin compaction at telomeric and pericentric repeats resulting in telomere shortening. In line with the effect of Suv39h1 overexpression Suv4-20h1 transgenic mice show reduced retarded papilloma formation during skin carcinogenesis. All those findings taken together confirm a role for Suv-HMTases in epigenetic control of telomeric heterochromatin and proliferation, identifying Suv39h1 and Suv4-20h1 as potential tumor suppressors in vivo