title: Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.
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.
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Tushar D
authors.initials: TD
authors.lastname: Bhagat
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Shizheng
authors.initials: S
authors.lastname: Huang
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Jihwan
authors.initials: J
authors.lastname: Park
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Palmer
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hu
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Niraj
authors.initials: N
authors.lastname: Shenoy
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Giricz
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Choudhary
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Ko
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: María C
authors.initials: MC
authors.lastname: Izquierdo
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
authors.forename: Ae Seo Deok
authors.initials: AS
authors.lastname: Park
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Nishanth
authors.initials: N
authors.lastname: Vallumsetla
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Remi
authors.initials: R
authors.lastname: Laurence
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Robert
authors.initials: R
authors.lastname: Lopez
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: the Department of Pathology, Montefiore Medical Center, Bronx, New York 10467.
authors.forename: James
authors.initials: J
authors.lastname: Pullman
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Justin
authors.initials: J
authors.lastname: Kaner
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gartrell
authors.affiliation: the Sloan Kettering Cancer Center, New York, New York 10065, and.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.affiliation: Eli Lilly, Indianapolis, Indiana 46221.
authors.forename: Bharvin
authors.initials: B
authors.lastname: Patel
authors.affiliation: Eli Lilly, Indianapolis, Indiana 46221.
authors.forename: Karim
authors.initials: K
authors.lastname: Benhadji
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Kith
authors.initials: K
authors.lastname: Pradhan
authors.affiliation: From the Albert Einstein College of Medicine, Bronx, New York 10461, amit.verma@einstein.yu.edu.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: the Renal Electrolyte and Hypertension Division, Department of Medicine and Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, ksusztak@mail.med.upenn.edu.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002292:Carcinoma, Renal Cell; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D004273:DNA, Neoplasm; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; C497762:Notch1 protein, mouse; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases
keywords: DNA methylation; Notch pathway; cancer biology; cancer therapy; renal physiology