Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cell biology Oncology

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

  • Text
  • PDF
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

×

Figure 1

Higher CSL expression in premalignant and malignant squamous cancer lesions.

Options: View larger image (or click on image) Download as PowerPoint
Higher CSL expression in premalignant and malignant squamous cancer lesi...
(A) Immunofluorescence analysis of CSL expression in epidermis of normal skin, with DAPI staining for cell identification. Similar analysis of normal skin samples from 2 more individuals is shown in Supplemental Figure 1A. n = 3 individuals. Scale bar: 25 μm. (B) Immunohistochemical analysis of CSL expression in normal oral epithelium. n = 1 individual. Scale bar: 125 μm. Dotted lines mark the border of the epidermal compartment relative to the underlying mesenchyme. (C) Immunohistochemical analysis of CSL expression in an AK (54) lesion and flanking normal (N) skin. Similar analysis of additional AK lesions and flanking skin is shown in Supplemental Figure 1B. n = 5 AK regions; n = 5 N regions. Right panel: CSL signal quantification of all AK patients. Data are shown as mean ± SEM, 2-tailed paired t test. Scale bars: 1000 μm (upper panels); 100 μm (lower panels). (D) Immunohistochemical analysis of CSL expression in oral SCC lesions and flanking dysplastic and normal tissue. For additional lesions, see Supplemental Figure 1C. n = 7 carcinoma; n = 4 dysplastic; n = 7 normal regions. Right panel: CSL signal quantification of all SCC patients. Data are shown as mean ± SEM, 1-way ANOVA with Dunnett’s test. Scale bars: 1000 μm (upper panels); 100 μm (lower panels). (E) Immunohistochemical analysis of CSL expression in tissue arrays of skin and oral SCC lesions in low- versus high-grade tumors (defined by invasion beyond submucosal tissue). Representative images are shown along with CSL signal quantification. Data are shown as mean ± SEM, 2-tailed unpaired t test. n = 8 low-grade skin lesions; n = 12 high-grade skin lesions; n = 18 low-grade oral lesions; n = 8 high-grade oral lesions. Scale bars: 200 μm. (C–E) **P < 0.005; ***P < 0.0005.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts