RASSF1 and the Hippo pathway
The biological significance of aberrant methylation in cancer (“driver” versus “passenger” methylation) is unclear (Kalari et al., 2010). Earlier, we identified and characterized the gene RASSF1A (Dammann et al., 2000). This gene undergoes methylation silencing in almost every type of human tumor (~1000 publications in PubMed). In the face of increasing numbers of cancer genome sequencing studies identifying mutations in critical genes, researchers are loosing sight of the breadth and significance of cancer-associated promoter hypermethylation. The RASSF1A pathway is a prime example highlighting the importance of epigenetic silencing events in tumors in the absence of frequent mutation of a gene. We identified RASSF1A as an upstream regulator of the Hippo tumor suppressor pathway (Guo et al., 2007). Interestingly, the one component of the Hippo pathway most frequently affected in human cancer is RASSF1A, which is silenced by promoter methylation in over 90% of human liver tumors, for example. Therefore, this promoter methylation is of high significance and we continue to study the biochemical function of RASSF1A and its related family members in the mammalian Hippo pathway and other tumor-relevant processes.
Dammann, R., Li, C., Yoon, J.-H., Chin, P.L., Bates, S., and Pfeifer, G.P. (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3, Nature Genet. 25, 315-319.
Guo, C., Tommasi, S., Liu, L., Yee, J.-K., Dammann, R., and Pfeifer, G.P. (2007) The RASSF1A tumor suppressor protein is a component of a mammalian complex analogous to the Drosophila Hippo/Salvador/Lats tumor suppressor network, Curr. Biol. 17, 700-705.
Kalari, S., and Pfeifer, G.P. (2010) Identification of driver and passenger DNA methylation in cancer by epigenomic analysis, Adv. Genet. 70, 277-308.
Pfeifer, G.P., Dammann, R., and Tommasi, S. (2010) RASSF proteins, Curr. Biol. 20, R344-R345.