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Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2018 Jun 01; Vol. 128 (6), pp. 2581-2599. Date of Electronic Publication: 2018 May 14. - Publication Year :
- 2018
-
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.
- Subjects :
- Animals
Biomarkers, Tumor genetics
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell pathology
Cell Line, Tumor
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics
Jumonji Domain-Containing Histone Demethylases genetics
Keratinocytes metabolism
Keratinocytes pathology
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Proteins genetics
Neoplasms, Experimental genetics
Neoplasms, Experimental pathology
Receptors, Notch genetics
Receptors, Notch metabolism
Biomarkers, Tumor metabolism
Carcinoma, Squamous Cell metabolism
Immunoglobulin J Recombination Signal Sequence-Binding Protein metabolism
Jumonji Domain-Containing Histone Demethylases metabolism
Neoplasm Proteins metabolism
Neoplasms, Experimental metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 128
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 29757189
- Full Text :
- https://doi.org/10.1172/JCI96915