Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.

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Version: Final published version
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Serval ID
serval:BIB_64DFBBAE75C2
Type
Article: article from journal or magazin.
Collection
Publications
Title
Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.
Journal
The Journal of clinical investigation
Author(s)
Al Labban D., Jo S.H., Ostano P., Saglietti C., Bongiovanni M., Panizzon R., Dotto G.P.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
01/06/2018
Peer-reviewed
Oui
Volume
128
Number
6
Pages
2581-2599
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment.
Keywords
Animals, Biomarkers, Tumor/genetics, Biomarkers, Tumor/metabolism, Carcinoma, Squamous Cell/genetics, Carcinoma, Squamous Cell/metabolism, Carcinoma, Squamous Cell/pathology, Cell Line, Tumor, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics, Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism, Jumonji Domain-Containing Histone Demethylases/genetics, Jumonji Domain-Containing Histone Demethylases/metabolism, Keratinocytes/metabolism, Keratinocytes/pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins/genetics, Neoplasm Proteins/metabolism, Neoplasms, Experimental/genetics, Neoplasms, Experimental/metabolism, Neoplasms, Experimental/pathology, Receptors, Notch/genetics, Receptors, Notch/metabolism, Signal Transduction, Cell Biology, Head & neck cancer, Lung cancer, Oncology, Skin cancer
Pubmed
Web of science
Open Access
Yes
Create date
17/05/2018 18:44
Last modification date
18/09/2019 6:10
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