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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [RNA-seq]

ABSTRACT: Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [RNA-seq]

PROVIDER: PRJNA529802 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8810745.fastq.gz	Fastqsanger.gz
	SRR8810746.fastq.gz	Fastqsanger.gz
	SRR8810747.fastq.gz	Fastqsanger.gz
	SRR8810748.fastq.gz	Fastqsanger.gz

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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

Project description:Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [ChIP-seq]

Project description:Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [ChIP-seq]

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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [RNA-seq]

Project description:Mutations in the DNA binding domain (DBD) of TP53 are often associated with the gain-of-function (GOF) of mutp53, resulting in pervasive transcription of chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Efforts to target this tumor-promoting function of mutp53 remain elusive. Here, we therapeutically exploit the GOF mechanisms of p53 codon 158 mutation, a DBD mutant found to be prevalent in lung squamous cell carcinoma. Using high throughput compound screening and combination analyses, we uncovered that mutp53R158G exhibits strong synergistic cytotoxicity to cisplatin-induced DNA stress and belinostat, a histone deacetylase inhibitor. This treatment regime acetylates mutp53, alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signalling and inducing apoptosis. This mechanistic intervention was validated with other acetylators of mutp53 and in several cancer models. Given that this transcriptional modulation and cytotoxic vulnerability appears inapt in p53 wild-type (WT) or null cells, our work provides a novel therapeutic opportunity in Arg158 15 -mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically

2020-02-26 | GSE129026 | GEO

Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation [ChIP-seq]

2020-02-26 | GSE128673 | GEO

Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation.

Project description:Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates I?B and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-?B) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically.

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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

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2020-02-26 | GSE129027 | GEO

Transcriptome analysis of polymorphic p53 codon 72 under genotoxic stress

Project description:We report the transcriptome data produced from isogenic polymorphic p53 codon 72 iPSCs under doxorubicin treatment. By inserting BAC DNA into one allele of the heterozygous polymorphic p53 codon 72, each clone expressed a p53 protein encoding P72 or R72 from another allele in which it was not inserted. The transcriptional regulation of p53 target genes was compared between the isogenic lines under doxorubicin treatment.

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2023-03-21 | PXD040993 |

p53 C-terminal acetylation modulates apoptotic program

Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.

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Transcriptome analysis of polymorphic p53 codon 72 under genotoxic stress

Project description:Transcriptome analysis of polymorphic p53 codon 72 under genotoxic stress

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