Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling
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
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
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Research Article Oncology

Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling

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

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Figure 4

KLHDC8A promotes the expression of ECM and extracellular signaling genes.

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KLHDC8A promotes the expression of ECM and extracellular signaling genes...
(A) Differentially expressed genes in GSC23 and GSC3028 transduced with shRNAs targeting KLHDC8A or a nontargeting control shRNA are displayed by volcano plot. Blue dots indicate genes downregulated in KLHDC8A knockdown cells at an adjusted P < 0.01 and log2 fold change less than −0.5. Red indicates genes upregulated following KLHDC8A knockdown at an adjusted P < 0.01 and log2 fold change greater than 0.5. (B) GSEA of GO pathways enriched or depleted following KLHDC8A knockdown in GSC23 and GSC3028 are displayed. Blue dots indicate enrichment in gene sets downregulated following KLHDC8A knockdown at an FDR < 0.15. (C) Top 6 downregulated receptor signaling signatures following KLHDC8A knockdown in GSC23 and GSC3028. Enriched gene signatures are plotted with normalized enrichment score. (D) Bubble plots showing the GSEA of gene sets positively or negatively correlated with KLHDC8A expression in TCGA glioblastoma HG-U133A data set. Blue dots indicate enrichment in gene sets negatively correlated with KLHDC8A expression. Red dots indicate enrichment in gene sets positively correlated with KLHDC8A expression. (E) GSEA of Hallmark gene sets correlated with KLHDC8A expression in TCGA glioblastoma HG-U133A data set are shown.