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KDM4A) Rescues 3P Haploinsufficiency

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KDM4A) Rescues 3P Haploinsufficiency Inhibition of Lysine Demethylase 4A (KDM4A) Rescues 3p Haploinsufficiency Ruhee Dere, Ph.D. 14th International VHL Medical Symposium Oct 29, 2020 Renal Cell Carcinoma – Loss of 3p Tumor Suppressors Co-deletion of multiple tumor suppressors on chromosome 3p contribute to renal cell carcinoma (RCC) 90% of clear cell renal cell carcinoma (ccRCC) have mono-allelic loss of Hsieh J et al., JCO, 2018 the epigenetic regulator SETD2 HistoneHistone Code Code Vs. Vs. Tubulin Tubulin Code Courtesy Dr. Verhey Laurence et al., Trends in Genetics, 2016 SETD2 – A Dual Chromatin & Tubulin Methyltransferase α-tub α-tubK40me3 DAPI Merge Zoom Li F. et al., Cell, 2013 Park IY. et al., Cell, 2016 • SETD2 writes the tri-methyl mark on histone H3 lysine 36 (H3K36me3) SETD2 GST GST GST SETD2 SETD2 • In vitro methylation assays show SETD2 can α -Tubulin methylate α-tubulin • Mass spec identified K40 of α-tubulin as the site for trimethylation Histone • Methyl lysine antibody specific for K40me3 polyMT depolyMT Histones recognized a methyl mark on spindle microtubules Park IY. et al., Cell, 2016 • Loss of Setd2 results in multiple mitotic defects and genomic instability Existence of Dual-Function Epigenetic Regulators Nucleus Cytoplasm Erasers Writers Erasers KDM4A Altered cytoskeleton Writers ?? Cell proliferation Gene Expression SETD2 Genomic stability DNA repair ?? Chromatin structure Migration & metastasis me me me me K40 Readers K40 PBRM1 Readers ?? KDM4A is a Cytoplasmic Protein hTERT RPE-1 HKC MEFs WCE N C CD44 HA-KDM4A WCE N C N C N C KDM4A KDM4A KDM4A Lamin A/C Lamin A/C Lamin A/C LDH LDH LDH • KDM4A is the corresponding demethylase that Li. GM, Cancer Res, 2013 erases the methyl mark laid by SETD2 on chromatin (H3K36me3) • KDM4A is a dioxygenase enzyme requiring Fe, α- ketoglutarate as co-factors for its activity • KDM4A localizes in the cytoplasm KDM4A Binds Methylated Tubulin A RPE1 B C hTERT RPE-1 D HEK293T cells WCE • KDM4A binds α-tubulin • KDM4A binds methylated IP: KDM4A Fold enrichment tubulin over IgG control Mass Spec Analysis • Tubulin 1A (TUB1A) is highly enriched in KDM4A immunoprecipitates KDM4A Demethylates Tubulin A B • Recombinant KDM4A Substrate: Substrate: Recombinant H3K36me3 Purified Tubulin (bovine) demethylates recombinant Recombinant - + Recombinant KDM4A KDM4A - + microtubules H3K36me3 K40me3 • Overexpression of a catalytically H3 (input) Tubulin (input) dead KDM4A (H188A mutant) fails to decrease methylation on C D microtubules • Loss of KDM4A increases K40me3 signal at the mitotic spindle E KDM4A Localizes at the MTOCs • KDM4A localizes at the poles of the mitotic spindle • KDM4A is a centrosome-associated protein that colocalizes with γ- tubulin at the MTOCs during mitosis • Localization of KDM4A at MTOCs is independent of SETD2 methylation on microtubules KDM4A Opposes SETD2- Mediated Methylation on MTs If KDM4A opposes the methyl mark on MTs laid by SETD2, then inhibition of KDM4A should rescue genomic defects associated with SETD2 haploinsufficiency. Chiang et al., Cancer Res, 2018 Loss of KDM4A Rescues Genomic Instability Associated with Mono-allelic Loss of Setd2 Summary • KDM4A is a cytoplasmic protein that binds α-tubulin KDM4A demethylates Erasers • KDM4A microtubules Altered cytoskeleton Writers ?? Cell proliferation SETD2 • KDM4A localizes to the MTOCs Genomic stability ?? Migration & metastasis of the mitotic spindle me me K40 Readers K40 PBRM1 ?? Summary KDM4A activity can be inhibited using the small molecule JIB-04 JIB-04 disrupts O2 binding JIB-04 in the catalytic domain of KDM4A Cascella B., et al., 2017, Chem. Commun. Acknowledgements University of Michigan Kristen Verhey, Ph.D. U.T. Southwestern Elisabeth Martinez, Ph.D. Pratim Chowdhury Dr. Rahul Jangid Research Associate Post-doctoral Fellow Vanderbilt University W. Kimryn Rathmell, M.D., Ph.D. Frank Mason, Ph.D. Baylor College of Medicine Cheryl L. Walker, Ph.D. Nicolas Young, Ph.D. Funding Sung Jung, Ph.D. VHL Alliance Gilson Longenbaugh Foundation.
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