PXD050328-1

PXD050328 is an original dataset announced via ProteomeXchange.

Title	HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer
Description	Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.
HostingRepository	PRIDE
AnnounceDate	2024-05-21
AnnouncementXML	Submission_2024-05-21_04:24:19.820.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Florian Meier
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-04 08:48:17	ID requested
⏵ 1	2024-05-21 04:24:20	announced

Dataset with its publication pending

submitter keyword: lipid peroxidation, proteomics, ferroptosis,HDACi

Prof. Dr. Florian Meier
contact affiliation	AG Functional Proteomics, University Hospital Jena
contact email	Florian.Meier-Rosar@med.uni-jena.de
lab head
Florian Meier
contact affiliation	Jena University Hospital
contact email	florian.meier@med.uni-jena.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD050328
     1. Label: PRIDE project
     2. Name: HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer