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

Autor: Seung-Hee Jo, Renato G. Panizzon, Paola Ostano, Dania Al Labban, G. Paolo Dotto, Massimo Bongiovanni, Chiara Saglietti
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Keratinocytes
Jumonji Domain-Containing Histone Demethylases
Notch signaling pathway
Mice
SCID
Biology
medicine.disease_cause
Proinflammatory cytokine
03 medical and health sciences
Mice
Mice
Inbred NOD
Cell Line
Tumor
medicine
Biomarkers
Tumor
Gene silencing
Animals
Humans
Transcription factor
Notch 1
Biomarkers
Tumor/genetics
Biomarkers
Tumor/metabolism
Carcinoma
Squamous Cell/genetics
Carcinoma
Squamous Cell/metabolism
Carcinoma
Squamous Cell/pathology
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
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
Receptors
Notch
General Medicine
Neoplasms
Experimental
3. Good health
Neoplasm Proteins
stomatognathic diseases
030104 developmental biology
Histone
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Cancer research
biology.protein
Carcinoma
Squamous Cell
Signal transduction
Carcinogenesis
Research Article
Zdroj: The Journal of clinical investigation, vol. 128, no. 6, pp. 2581-2599
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: