PXD019999

PXD019999 is an original dataset announced via ProteomeXchange.

Title	p53 C-terminal acetylation modulates apoptotic program
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:32:06.787.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2020-06-24 07:07:19	ID requested
1	2022-02-15 13:15:25	announced
⏵ 2	2024-10-22 05:32:08	announced	2024-10-22: Updated project metadata.

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]

submitter keyword: Parallel Reaction Monitoring, DNA damage response (DDR), C-terminus, mitochondria, apoptosis, Acetylation, p53

Sara Rossana Zanivan
contact affiliation	CRUK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
contact email	s.zanivan@beatson.gla.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD019999

PRIDE project URI

• PRIDE
  1. PXD019999
     1. Label: PRIDE project
     2. Name: p53 C-terminal acetylation modulates apoptotic program