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bioRxiv · 10.1101/2025.09.16.676559

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.
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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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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. Gain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma. https://doi.org/10.1101/2025.09.16.676559

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