Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer

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

doi:10.1074/jbc.m116.745208

Cited by 45 publications

(45 citation statements)

References 31 publications

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“…DNMTs and other methyl-CpG-binding proteins (e.g., MBD2, MBD3 and MeCP2) recruit histone modifiers (e.g., histone deacetylase and chromatin remodelling complexes) to the methylated promoter region [ 166 , 167 , 168 ], and deacetylates histones 3 and 4 and stimulates chromatin condensation and gene silencing [ 6 , 169 ]. Furthermore, many studies have pointed out the occurrence of CpGs in other genomic regions that are essential for gene regulation including enhancers, repressors and regulatory regions within gene body [ 6 , 170 , 171 , 172 , 173 , 174 ].…”

Section: Epigenetics Of Ccrccmentioning

confidence: 99%

“…Likewise, JAG1 , was aberrantly hypomethylated in ccRCCs, resulting in overexpression of the JAG1 , a ligand in NOTCH signaling. The loss of DNA methylation on the JAG1 locus coincided with H3K4me1 chromatin modification at the active enhancer region [ 174 ]. Using high-resolution assays, additional studies uncovered that transcribed regions in gene body are highly methylated and the degree of methylation is positively correlated with level of expression proposing that transcribed region of gene methylation may be crucial in transcriptional regulation [ 69 , 187 , 188 , 189 , 190 , 191 ].…”

Section: Epigenetics Of Ccrccmentioning

confidence: 99%

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Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

Mehdi

Riazalhosseini

2017

IJMS

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Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC.

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Section: Epigenetics Of Ccrccmentioning

confidence: 99%

Section: Epigenetics Of Ccrccmentioning

confidence: 99%

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

Mehdi

Riazalhosseini

2017

IJMS

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“…In a simplified scenario, this bivalent chromatin, usually found in embryonic stem cells, maintains the developmental genes in a poised state for later activation or repression in a time and context-specific manner. Moreover, CSCs re-activate the so-called embryonic signaling pathways, including Wnt/β-catenin, Hedgehog and Notch, but also IL6/JAK/STAT3, NFκB, and PI3K/AKT, which in turn control the epigenetic dynamics in the cells in a positive feedback loop [49][50][51][52][53][54].…”

Section: Epigenetic Reprogramming: the Common Switch Through Tumor Dementioning

confidence: 99%

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Citron

Fabris

2020

Cancers

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Extensive efforts recently witnessed the complexity of cancer biology; however, molecular medicine still lacks the ability to elucidate hidden mechanisms for the maintenance of specific subclasses of rare tumors characterized by the silent onset and a poor prognosis (e.g., ovarian cancer, pancreatic cancer, and glioblastoma). Recent mutational fingerprints of human cancers highlighted genomic alteration occurring on epigenetic modulators. In this scenario, the epigenome dependency of cancer orchestrates a broad range of cellular processes critical for tumorigenesis and tumor progression, possibly mediating escaping mechanisms leading to drug resistance. Indeed, in this review, we discuss the pivotal role of chromatin remodeling in shaping the tumor architecture and modulating tumor fitness in a microenvironment-dependent context. We will also present recent advances in the epigenome targeting, posing a particular emphasis on how this knowledge could be translated into a feasible therapeutic approach to individualize clinical settings and improve patient outcomes.

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“…LY3039478 (GSI, Eli‐Lilly) has recently shown potency in inhibiting clear cell renal cell carcinoma growth in vitro and in vivo in a murine xenograft . Patients are currently being recruited into four phase I clinical trials investigating LY3039478's effect alone or with adjuvant therapies on solid tumors and T‐ALL.…”

Section: Strategies For Notch Inhibitionmentioning

confidence: 99%

Perspectives on the discovery of NOTCH2‐specific inhibitors

et al. 2017

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The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side-effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch-specific small molecule inhibitors targeting the anti-NOTCH2 antibody-binding epitopes or the "S2-Leu-plug-binding site" using a computer-aided drug discovery approach.

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Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer

Abstract: Edited by Alex Toker

Cited by 45 publications

References 31 publications

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Perspectives on the discovery of NOTCH2‐specific inhibitors

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