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
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
Histone methyltransferases require metabolic cofactors
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
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
Oncohistone mutations serve as pan-methyltransferase inhibitors
M M
R27
A KSAPSTGGvKKP…
H3.3
31Me Me
*36
…
Lewis, Science, 2013
Inhibition of SETD2 results in altered SAM metabolism
SETD2 inhibition Next steps: determine SAM/GSH metabolite
levels in UTSW SPORE patient samples
SAM GSH
SETD2 expression alters transcription in ccRCC cell lines
Dual Chromatin and Cytoskeletal Remodeling by SETD2Walker Lab – Cell 2016
SETD2 expression alters growth and migration in ccRCC cell lines
But decreases cell migration
SETD2 expression increasesgrowth rate…
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
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