Chromatin dysregulation and metabolism in ccRCC · 2019-12-12 · Kidney cancer is a disease of...
Transcript of Chromatin dysregulation and metabolism in ccRCC · 2019-12-12 · Kidney cancer is a disease of...
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Chromatin dysregulationand metabolism in ccRCC
Laura Banaszynski, PhD
UT Southwestern Medical Center
@BanaszynskiLab
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Kidney cancer is a disease of chromatin dysregulation
De Cubas and Rathmell, Nat Rev Uro, 2018
Genes TCGA Cohort
Tumors With Mutation (%)
VHL 52.3
PBRM1 32.9
SETD2 11.5
BAP1 10.1
MTOR 6
TCEB1 0.7
PIK3CA 2.9
KDM5C 6.7
TP53 2.2
PTEN 4.3
Brugarolas, J Clin Oncol, 2014
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Histone methyltransferases require metabolic cofactors
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SETD2 mutation is mutually exclusive with amplification of MAT1A/2A
cBioportal, TCGA ccRCC provisional data set
Hypothesis: Upregulation of SAM synthesis substitutes for loss of SETD2 in ccRCC
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Hypothesis:SETD2 mutation contributes to metabolic dysregulation in ccRCC
Significance:SETD2 mutation status may confer metabolic or other synthetic lethalities
Impact:Better understanding of SETD2 function will inform and improve patient treatment and outcomes
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Oncohistone mutations serve as pan-methyltransferase inhibitors
M M
R27
A KSAPSTGGvKKP…
H3.3
31Me Me
*36
…
Lewis, Science, 2013
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Inhibition of SETD2 results in altered SAM metabolism
SETD2 inhibition Next steps: determine SAM/GSH metabolite
levels in UTSW SPORE patient samples
SAM GSH
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SETD2 expression alters transcription in ccRCC cell lines
Dual Chromatin and Cytoskeletal Remodeling by SETD2Walker Lab – Cell 2016
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SETD2 expression alters growth and migration in ccRCC cell lines
But decreases cell migration
SETD2 expression increasesgrowth rate…
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Acknowledgements
Haitao Mao, PhD Shilpa Dhar Aishwarya Sundaresan, MS
UTSW KCPJim BrugarolasYi-Feng GuPayal KapurRalph DeBerardinisRenee McKayTao Wang
Funding: Simmons Comprehensive Cancer Center @ UTSW
UTSW KCP SPORE
DOD KCRP
@BanaszynskiLab