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Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B
Dania Al Labban, … , Renato Panizzon, G. Paolo Dotto
Dania Al Labban, … , Renato Panizzon, G. Paolo Dotto
Published May 14, 2018
Citation Information: J Clin Invest. 2018;128(6):2581-2599. https://doi.org/10.1172/JCI96915.
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Research Article Cell biology Oncology

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

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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.

Authors

Dania Al Labban, Seung-Hee Jo, Paola Ostano, Chiara Saglietti, Massimo Bongiovanni, Renato Panizzon, G. Paolo Dotto

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Figure 5

Tumor modulatory effects of increased versus suppressed CSL expression on SCC cells.

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Tumor modulatory effects of increased versus suppressed CSL expression o...
(A) SCC13 and FaDu cells stably infected with lentiviral vector for doxycycline-inducible Myc-tagged CSL or empty vector control (pIND20) were injected in parallel into ears of NOD/SCID mice. Shown are tumor volumes at day of sacrifice (left panel), with representative images for 1 pair of mouse ears (right panel) and corresponding H&E staining of SCC13 lesions. n = 7 mice for SCC13 lesions; n = 4 mice for FaDu lesions. (B) SCC13, SCCO22, and SCCO28 cells infected with CSL-silencing lentivirus versus empty vector control were injected into ears of NOD/SCID mice. Shown are tumor volumes (upper panels) with representative images of 1 pair of mouse ears (lower panels), and corresponding H&E staining of SCCO22 lesions (right panels). Scale bars: 250 μm. n = 6 mice for SCC13 lesions; n = 6 mice for SCCO22 lesions; n = 6 mice for SCCO28 lesions from experiment 1 (Exp.1) and 5 mice from experiment 2. (A and B) Scale bars: 250 μm. Data are shown as mean ± SEM. *P < 0.05; ***P < 0.0005, 1-tailed paired t test.

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