PXD056852

PXD056852 is an original dataset announced via ProteomeXchange.

Title	NNMT mediates sensitivity to NAD(H) lowering agents in prostate cancer cells with mesenchymal phenotype
Description	Castration-resistant prostate cancer (CRPC) refers to a population of prostate cancer patients who are no longer responsive to androgen deprivation therapy (ADT). Metastatic CRPC is currently lethal, underscoring the urgent need to identify novel therapeutical targets to reverse disease outcome. Unresponsiveness to ADT is multifactorial and often associated with prostate cancer cell’s plasticity, leading to the arise of several CRPC subtypes, which should be individually address for the identification of targetable vulnerabilities. Particularly, the development of mesenchymal stem-like phenotypes is associated with CRPC. The Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway, whose deregulation is associated with CRPC. Here we showed that YAP depletion in mesenchymal stem-cell like PC cells leads to the downregulation of proteins previously associated with epithelial to mesenchymal transdifferentiation (EMT), including N-methylnicotinamide transferase (NNMT). NNMT is also involved in cellular energetics, by competing with nicotinamide phosphoribosyltransferase (NAMPT) for nicotinamide. Thus, we found that mesenchymal-like prostate cancer cells with upregulation of NAMPT, but not epithelial ones, are sensitive to NAMPT inhibition (FK866). NNMT depletion counteracts FK866 toxicity by maintaining cellular nicotinamide levels. Moreover, we identified NNMT as a marker of a subtype of CRPC with stem-cell properties (CRPC-SCL) in which YAP is a main targetable vulnerability. Transcriptomics analysis of a murine-derived prostate cancer cell line exposed to stem cell conditions (DVL3-SCM), unraveled a strong upregulation of NNMT transcripts, in comparison to the parental counterpart (DVL3-PAR). DVL3-SCM presented an increased mesenchymal phenotype and aggressiveness in vitro. In conclusion, we found a specific vulnerability of a subpopulation of CRPC showing that NAMPT inhibition can be an effective molecular targeting strategy to overcome therapy resistant metastatic PC cells with mesenchymal, YAP dependent, phenotype. Notably, the efficacy of NAMPT targeting is potentiated by its dependency on YAP NNMT expression.
HostingRepository	PRIDE
AnnounceDate	2025-02-24
AnnouncementXML	Submission_2025-02-24_01:32:27.257.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD056852
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Romina Belli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-16 04:50:34	ID requested
⏵ 1	2025-02-24 01:32:27	announced

10.6019/PXD056852;

submitter keyword: NNMT, EMT, CRPC-SCL,NAMPT, YAP, FK866, Stemness

Alessandro Provenzani
contact affiliation	University of Trento, Department CIBIO - Laboratory of Genomic Screening, Trento, Italy
contact email	alessandro.provenzani@unitn.it
lab head
Romina Belli
contact affiliation	University of Trento
contact email	romina.belli@unitn.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056852
     1. Label: PRIDE project
     2. Name: NNMT mediates sensitivity to NAD(H) lowering agents in prostate cancer cells with mesenchymal phenotype