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
Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling
Derrick Lee, … , David R. Raleigh, Jeremy N. Rich
Derrick Lee, … , David R. Raleigh, Jeremy N. Rich
Published November 17, 2022
Citation Information: J Clin Invest. 2023;133(2):e163592. https://doi.org/10.1172/JCI163592.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 5

Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling

  • Text
  • PDF
Abstract

Glioblastoma ranks among the most aggressive and lethal of all human cancers. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain–containing gene, specifically Kelch domain containing 8A (KLHDC8A) with a previously unknown function as an epigenetically driven oncogene. Targeting KLHDC8A decreased GSC proliferation and self-renewal, induced apoptosis, and impaired in vivo tumor growth. Transcription factor control circuitry analyses revealed that the master transcriptional regulator SOX2 stimulated KLHDC8A expression. Mechanistically, KLHDC8A bound chaperonin-containing TCP1 (CCT) to promote the assembly of primary cilia to activate hedgehog signaling. KLHDC8A expression correlated with Aurora B/C Kinase inhibitor activity, which induced primary cilia and hedgehog signaling. Combinatorial targeting of Aurora B/C kinase and hedgehog displayed augmented benefit against GSC proliferation. Collectively, superenhancer-based discovery revealed KLHDC8A as what we believe to be a novel molecular target of cancer stem cells that promotes ciliogenesis to activate the hedgehog pathway, offering insights into therapeutic vulnerabilities for glioblastoma treatment.

Authors

Derrick Lee, Ryan C. Gimple, Xujia Wu, Briana C. Prager, Zhixin Qiu, Qiulian Wu, Vikas Daggubati, Aruljothi Mariappan, Jay Gopalakrishnan, Matthew R. Sarkisian, David R. Raleigh, Jeremy N. Rich

×

Figure 5

KLHDC8A promotes hedgehog signaling pathways in GSCs.

Options: View larger image (or click on image) Download as PowerPoint
KLHDC8A promotes hedgehog signaling pathways in GSCs.
(A and B) qPCR ana...
(A and B) qPCR analysis of mRNA expression of hedgehog pathway genes SHH, SMO, and GLI1 in 2 GSCs and matched DGCs. n = 3. Quantitative data from 3 independent experiments are shown as mean ± SD. Statistical analysis was performed using Student’s t test with the Holm-Šidák multiple test correction. (C) Immunoblot showing the protein expression of Shh and Gli1 in 2 matched pairs of GSCs and DGCs is shown. SOX2 was used to determine the stemness of GSCs. GFAP was used to determine the differentiation of GSCs. β-Actin was used as the loading control. (D and E) qPCR analysis of KLHDC8A, SHH, and GLI1 mRNA expression in GSC387 and GSC23 following knockdown of KLHDC8A. n = 4. Quantitative data from 4 independent experiments are shown as mean ± SD. Statistical analysis was performed using 2-way ANOVA with the Šidák multiple test correction. (F) Immunoblot showing the protein expression of GLI1 and SHH upon KLHDC8A knockdown. (G and H) qPCR analysis of mRNA expression of GLI1 target genes in GSC387 (G) and GSC23 (H). n = 4. Quantitative data from 4 independent experiments are shown as mean ± SD. Statistical analysis was performed using Student’s t test with Dunnett’s multiple test correction. (I) Concentration-response curves of 2 matched pairs of GSCs and DGCs to SMO inhibitor Sonidegib over a 6-day time course. ***P < 0.001, ****P < 0.0001.

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

Sign up for email alerts

Posted by 10 X users
16 readers on Mendeley
See more details