Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer

Tushar D. Bhagat, Yiyu Zou, Shizheng Huang, Jihwan Park, Matthew B. Palmer, Caroline Hu, Weijuan Li, Niraj Shenoy, Orsolya Giricz, Gaurav Choudhary, Yiting Yu, Yi An Ko, María C. Izquierdo, Ae Seo Deok Park, Nishanth Vallumsetla, Remi Laurence, Robert Lopez, Masako Suzuki, James Pullman, Justin KanerBenjamin Gartrell, A. Ari Hakimi, John M. Greally, Bharvin Patel, Karim Benhadji, Kith Pradhan, Amit Verma, Katalin Susztak

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo. Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo. In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)837-846
Number of pages10
JournalJournal of Biological Chemistry
Volume292
Issue number3
DOIs
StatePublished - Jan 20 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Bhagat, T. D., Zou, Y., Huang, S., Park, J., Palmer, M. B., Hu, C., Li, W., Shenoy, N., Giricz, O., Choudhary, G., Yu, Y., Ko, Y. A., Izquierdo, M. C., Park, A. S. D., Vallumsetla, N., Laurence, R., Lopez, R., Suzuki, M., Pullman, J., ... Susztak, K. (2017). Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer. Journal of Biological Chemistry, 292(3), 837-846. https://doi.org/10.1074/jbc.M116.745208