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PXD019999

PXD019999 is an original dataset announced via ProteomeXchange.

Dataset Summary
Titlep53 C-terminal acetylation modulates apoptotic program
DescriptionAdvanced 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:32:06.787.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSergio Lilla
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; acetylated residue
InstrumentLTQ Orbitrap Velos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-06-24 07:07:19ID requested
12022-02-15 13:15:25announced
22024-10-22 05:32:08announced2024-10-22: Updated project metadata.
Publication List
10.1002/1878-0261.13060;
Marx C, Sonnemann J, Beyer M, Maddocks ODK, Lilla S, Hauzenberger I, Pi, é, e-Staffa A, Siniuk K, Nunna S, Marx-Bl, ü, mel L, Westermann M, Wagner T, Meyer FB, Thierbach R, Mullins CS, Kdimati S, Linnebacher M, Neri F, Heinzel T, Wang ZQ, Kr, ä, mer OH, Mechanistic insights into p53-regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells. Mol Oncol, 15(12):3404-3429(2021) [pubmed]
Keyword List
submitter keyword: Parallel Reaction Monitoring, DNA damage response (DDR), C-terminus, mitochondria, apoptosis, Acetylation, p53
Contact List
Sara Rossana Zanivan
contact affiliationCRUK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
contact emails.zanivan@beatson.gla.ac.uk
lab head
Sergio Lilla
contact affiliationProteomics
contact emails.lilla@beatson.gla.ac.uk
dataset submitter
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Dataset FTP location
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