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Superenhancer-activation of KLHDC8A Drives Glioma Ciliation and Hedgehog signaling

ABSTRACT: Superenhancer-activation of KLHDC8A Drives Glioma Ciliation and Hedgehog signaling

PROVIDER: PRJNA857022 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20048665_1.fastq.gz	Fastqsanger.gz
	SRR20048665_2.fastq.gz	Fastqsanger.gz
	SRR20048666_1.fastq.gz	Fastqsanger.gz
	SRR20048666_2.fastq.gz	Fastqsanger.gz
	SRR20048667_1.fastq.gz	Fastqsanger.gz

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Superenhancer-activation of KLHDC8A Drives Glioma Ciliation and Hedgehog signaling

Project description:Glioblastoma ranks among the most aggressive and lethal of all human cancers, with poor responses to all therapeutic modalities. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Identification of GSC vulnerabilities may provide novel therapeutic targets for treating glioblastoma. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain-containing gene (KLHDC8A) with a previously unknown function as an epigenetically driven oncogene. Targeting KLHDC8A decreased GSC proliferation, reduced sphere formation, induced apoptosis, and impaired in vivo tumor growth. Transcription factor control circuitry analyses revealed that the master transcriptional regulator SOX2 contributes to KLHDC8A expression. Mechanistically, KLHDC8A functions in the assembly of primary cilia via interactions with Chaperonin-containing TCP1 (CCT) and establishes a platform for a critical stem-specific signaling node through the Hedgehog pathway. Furthermore, we identified that Hedgehog and Aurora B/C Kinase signaling are complementary in GSCs, and dual inhibition synergistically inhibits GSC proliferation. Collectively, superenhancers enrich for essential mediators of cellular identity and offer a novel regulatory mechanism whereby promotion of ciliogenesis establishes and maintains a core GSC signaling node via the Hedgehog pathway, potentially offering insights into therapeutic vulnerabilities for glioblastoma treatment.

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Superenhancer activation of KLHDC8A drives glioma ciliation and hedgehog signaling.

Project description: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.

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