SETD2 and Clear Cell Renal Cell Carcinoma Abby Kepley.
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Transcript of SETD2 and Clear Cell Renal Cell Carcinoma Abby Kepley.
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SETD2 and Clear Cell Renal Cell Carcinoma
Abby Kepley
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SETD2 is a Histone Methyltransferase of H3K36me3
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Post-translational modifications of H3K36 are important in regulating DNA
structure and expression throughout the genome
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Multiple domains within SETD2 contribute to its enzymatic function
S-adenosylmethionine (SAM)
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SETD2/HYPB is required for murine embryonic vascular remodeling
Whole-mount IHC with PECAM-1 antibody
In vitro tube formation assay with siRNA
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Clear Cell Renal Cell Carcinoma is the most common form of RCC
• ~75% of renal cell carcinomas are ccRCC
• There are both hereditary and sporadic forms
• 1/3 of patients present with locally advanced or metastatic disease
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Tumor suppressors VHL, BAP1, SETD2, and PBRM1 are commonly mutated in
ccRCC
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Loss of SETD2 function leads to impaired signaling in the DNA damage response
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It also leads to inactivation of p53
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The role of SETD2 in homologous repair
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Treatment options for ccRCC
• There has yet to be a targeted therapy for histone methyltransferases to reach clinical trials.
• Current Therapies Include:• Local: nephrectomy, EBRT• Cytokine Therapy: interferon-alpha, IL-2• Targeted: Sunitinib, Sorafenib
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SourcesPfister, S. X. (2014). SETD2-Dependent Histone H3K36 Trimethylation Is Required for Homologous Recombination Repair and Genome Stability. Cell Reports, 7(6), 2006–2018. doi: http://dx.doi.org/10.1016/j.celrep.2014.05.026
Hu, M. (2010). Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. PNAS, 107(7), 2956–2961.
Larkin, J. (2012). Epigenetic regulation in RCC: opportunities for therapeutic intervention? Nature Reviews, 9, 147–155. doi: doi:10.1038/nrurol.2011.236
Hakimi, A. (2013). Clinical and Pathologic Impact of Select Chromatin-modulating Tumor Suppressors in Clear Cell Renal Cell Carcinoma. European Urology, 63(5), 848–854. doi:http://dx.doi.org/10.1016/j.eururo.2012.09.005
Carvalho, S. (2014). SETD2 is required for DNA double-strand break repair and activation of the p53- mediated checkpoint. eLIFE, 1–19. doi:10.7554/eLife.02482
National Cancer Institute. (2015). Renal Cell Cancer Treatment (PDQ®). Retrieved from http://www.cancer.gov/cancertopics/pdq/treatment/renalcell/HealthProfessional/page8
Ramnani, D. (2015). Clear Cell Renal Cell Carcinoma. Retrieved from http://www.webpathology.com/image.asp?case=66&n=10
SMART. (2014). PostSET. Retrieved from http://smart.embl-heidelberg.de/smart/do_annotation.pl?BLAST=DUMMY&DOMAIN=PostSET
SMART. (2014). SET. Retrieved from http://smart.embl-heidelberg.de/smart/do_annotation.pl?BLAST=DUMMY&DOMAIN=SET
UniProt Consortium. (2015). Q9BYW2 - SETD2_HUMAN. Retrieved from http://www.uniprot.org/uniprot/Q9BYW2
Fernandes de Almeida, S. (2011). Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36. Nature Structural & Molecular Biology, 18, 977–983. doi:10.1038/nsmb.2123
Wagner, E. (2014). Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol . , 13(2), 1–26. doi:10.1038/nrm3274