biostudies-literatureUnknownZhang YNINDS NIH HHSNCI NIH HHSGain-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 HIF1α as a key LINC00643 interactor. Under hypoxia, LINC00643 repressed HIF1α expression and its target genes by interacting with the HIF1α enhancer. Knockdown of GOF-MUT-p53 upregulated LINC00643 and reduces HIF1α, 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 HIF1α pathway.bioRxiv : the preprint server for biology2025.09.16.676559https://www.ebi.ac.uk/biostudies/studies/S-EPMC12458236biostudies-literatureGain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma.PMC12458236R21 NS122136R01 NS122222U01 CA220841P30 CA044579Abounader RReon BSun YHolland EGrello CDube CJYuan FSaha SMarcinkiewicz PZhang YDutta AGibert MKChief DHudson KfalseGain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma.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 HIF1α as a key LINC00643 interactor. Under hypoxia, LINC00643 repressed HIF1α expression and its target genes by interacting with the HIF1α enhancer. Knockdown of GOF-MUT-p53 upregulated LINC00643 and reduces HIF1α, 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 HIF1α pathway.2025-01-01T00:00:00Z2025 Sep2026-05-02T03:18:11.85Z2026-05-02T03:09:59.555ZS-EPMC124582364100084510.1101/2025.09.16.676559