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