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

The Journal of Clinical Investigation
Dania Al LabbanG Paolo Dotto

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, a...Continue Reading

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Datasets Mentioned

BETA
GSE102762
GSE102761

Methods Mentioned

BETA
xenograft
RNA-seq
PCR
laser capture microdissection
ChIP-seq
ChIP
circumcision
transfection

Software Mentioned

DAVID
GSAA
TopHat
Trimmomatic
ImageJ
GSEA
HTSeq
Integrative Genomics Viewer (
SeqSP Analysis ( GSAA )
DeSeq2

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