Clear Cell Renal Cell Carcinoma and the Novel Tumor Suppressor SETD2 Histological subtypes of RCC show unique chromosomal abnormalities Clear Cell RCC nodular growth with areas of hemorrhage and necrosis 3p deletions Papillary RCC solid white mass Trisomy 7 and 17, loss of Y Chromophobe RCC expansile mass with a solid yellowbrown cut surface Loss of multiple chromosomes 1, 2, 6, 10, ccRCC lines show lack of solid tumor hallmarks such as RAS, BRAF, TP53, PTEN and EGFR Inactivation of the VHL is not sufficient to cause ccRCC in mice ccRCC is characterized by LOH of chromosome 3 International Journal of Cancer Volume 125, Issue 10, pages 2342-2348, 11 JUN 2009 DOI: 10.1002/ijc.24642 http://onlinelibrary.wiley.com/doi/10.1002/ijc.24642/full#fig1 Histones organize DNA, regulate expression, and can be modified During transcription, histones are transiently both modified and exchanged SETD2 is a non-redundant H3K36specific trimethyltransferase SETD2 regulates cryptic transcription at internal exons SETD2 is necessary for chromatinremodeler FACT’s recruitment Knockdown of SETD2 decreases H2B occupancy in internal exons Loss of SETD2 affects vascular remodeling in mice Changes in SETD2 alter global gene expression References 1. 2. 3. 4. 5. 6. 7. 8. 9. Kleymenova, E. "Susceptibility to Vascular Neoplasms but No Increased Susceptibility to Renal Carcinogenesis in Vhl Knockout Mice." Carcinogenesis 25.3 (2003): 309-15. Duns, Gerben, Inge Van Duivenbode, Jan Osinga, Harrie Hollema, Eva Van Den Berg-De Ruiter, Robert M.W. Hofstra, and Klaas Kok. "Histone Methyltransferase Gene SETD2, a Novel Tumor Suppressor Gene in Clear Cell Renal Cell Carcinoma."Cancer Genetics and Cytogenetics 203.1 (2010): 45. Buning, Ruth, Wiepke Koopmans, Heinz Neumann, Jason Chin, and John Van Noort. "Regulation of Nucleosome Conformational Dynamics by Post-Translational Histone Modifications Studied with Single-Pair FRET." Biophysical Journal 98.3 (2010): 475a. Berger, S.L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 Carvalho, Sílvia, et al. "Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription." Nucleic acids research 41.5 (2013): 2881-2893. "Pathology of Clear Cell Renal Cell Carcinoma ." Pathology of Clear Cell Renal Cell Carcinoma. N.p., n.d. Web. 17 Apr. 2013. Hu, M., X.-J. Sun, Y.-L. Zhang, Y. Kuang, C.-Q. Hu, W.-L. Wu, S.-H. Shen, T.-T. Du, H. Li, F. He, H.-S. Xiao, Z.-G. Wang, T.-X. Liu, H. Lu, Q.-H. Huang, S.-J. Chen, and Z. Chen. "Histone H3 Lysine 36 Methyltransferase Hypb/Setd2 Is Required for Embryonic Vascular Remodeling." Proceedings of the National Academy of Sciences 107.7 (2010): 2956-961. Sun, X.-J. "Identification and Characterization of a Novel Human Histone H3 Lysine 36-specific Methyltransferase." Journal of Biological Chemistry 280.42 (2005): 35261-5271. Chen, Meng, et al. "Genome‐wide profiling of chromosomal alterations in renal cell carcinoma using high‐density single nucleotide polymorphism arrays."International Journal of Cancer 125.10 (2009): 2342-2348.