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Gain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma

Zhang, Y.; Yuan, F.; Gibert, M. K.; Dube, C. J.; Hudson, K.; Grello, C.; Reon, B.; Saha, S.; Sun, Y.; Marcinkiewicz, P.; Dutta, A.; Chief, D.; Holland, E.; Abounader, R.

2025-09-18 cancer biology
10.1101/2025.09.16.676559 bioRxiv
Show abstract

Gain-of-function mutations of p53 (GOF-MUT-p53) act as oncogenes by regulating gene transcription. We screened for the genome-wide transcriptional targets of GOF-MUT-p53 in glioblastoma (GBM) and found that a significant subset of them were long non-coding RNAs (lncRNA). Among these, LINC00643 was strongly repressed by GOF-MUT-p53 but not wild-type p53. LINC00643 was downregulated in GBM and low-grade glioma and correlated with patient survival. LINC00643 and its conserved third exon (Exon3) suppressed GBM cell proliferation, migration, invasion, stem cell self-renewal, and in vivo tumor growth Mechanistically, ChIRP-seq identified HIF1 as a key LINC00643 interactor. Under hypoxia, LINC00643 repressed HIF1 expression and its target genes by interacting with the HIF1 enhancer. Knockdown of GOF-MUT-p53 upregulated LINC00643 and reduces HIF1, revealing a regulatory axis. These findings show extensive regulation of lncRNAs by GOF-MUT-p53 and uncover a novel mechanism by which GOF-MUT-p53 drives GBM through repression of LINC00643 and dysregulation of the HIF1 pathway.

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