Details

Autor(en) / Beteiligte

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

Titel

Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling

Ist Teil von

• The Journal of clinical investigation, 2023-01, Vol.133 (2), p.1-17

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.