CBX6 and CA9 as predictive indicators and therapeutic targets in GBM

TL;DR

This study identifies CBX6 and CA9 as important factors in glioblastoma tumor growth and suggests they could be used for treatment.

Contribution

The study reveals CBX6 and CA9 as novel therapeutic targets and predictive indicators in glioblastoma under hypoxic conditions.

Findings

CBX6 downregulation under hypoxia is linked to higher-grade tumors and worse survival in glioblastoma.

CA9 upregulation by hypoxia supports tumor growth and treatment resistance in glioblastoma.

CBX6 binds to the CA9 promoter, suggesting it regulates CA9 expression in glioblastoma cells.

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor that, partly due to its hypoxic tumor microenvironment (TME), is extremely difficult to treat. In our study, RNA sequencing and quantitative reverse-transcription PCR (qRT-PCR) analysis identified differential expression of chromobox 6 (CBX6) and carbonic anhydrase 9 (CA9) in GBM cells under hypoxic conditions. Downregulation of CBX6, a member of the Polycomb group proteins, occurs under hypoxic conditions and is associated with higher-grade tumors and worse patient survival. Here, we show that silencing CBX6 in GBM cells promotes proliferation, migration, and invasion, while its overexpression yields the opposite effects, indicating its role as a negative regulator of tumor aggressiveness. CA9, upregulated by hypoxia, contributes to an acidic environment supporting tumor growth, a more aggressive GBM phenotype, and treatment resistance. Our qRT-PCR and short hairpin RNA (shRNA)-mediated knockdown experiments demonstrate an inverse relationship between CBX6 and CA9 expression across various human and murine GBM cell lines. Chromatin immunoprecipitation (ChIP) assays with multiple primers confirmed that CBX6 binds to the CA9 promotor, suggesting that CBX6 regulates CA9 expression. Our findings highlight CBX6 and CA9 as potential therapeutic targets, offering insights into GBM biology and the response to hypoxia.

This research highlights CBX6 and CA9 as key regulators involved in hypoxia-driven glioblastoma biology. By linking epigenetic regulation and metabolic adaptation to tumor severity, these results identify potential molecular targets and support novel therapeutic approaches for a disease with few effective treatments.

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