PXD018410

PXD018410 is an original dataset announced via ProteomeXchange.

Title	The Tumor Suppressor FLCN Regulates Glycolysis by Specifically Binding and Inhibiting Lactate Dehydrogenase-A
Description	The “Warburg effect” describes the use of aerobic glycolysis by cancer cells to fuel their growth. Lactate dehydrogenase-A (LDHA) is key to this process and catalyzes the interconversion of pyruvate and lactate. Here we used a proteomic approach to identify LDHA as a binding partner of the tumor suppressor FLCN. Canonically, LDHA is thought to be a substrate-regulated enzyme, however our data show that FLCN uncompetitively inhibits LDHA activity by restricting movement of its active site loop. This inhibition appears to be critical in normal cells, as we show FLCN binds to and tightly regulates LDHA activity in order to preserve metabolic homeostasis. Pathogenic mutations of FLCN are associated with LDHA hyperactivity and kidney tumor formation, suggesting a mechanism for FLCN tumor suppressive function. We have identified a cell-permeant ten amino acid peptide based on the FLCN sequence that enters these tumors and inhibits LDHA ex vivo. In a broader context, renal cell carcinomas experience the Warburg effect and show FLCN dissociation from LDHA. Cells that experience this metabolic shift depend on the hyperactivity of LDHA, as previous work has shown attenuation or inhibition of LDHA leads to programmed cell death. Treating these cells with the FLCN-derived peptide causes apoptosis, strongly suggesting that the glycolytic shift of cancer cells is the result of FLCN inactivation or disassociation from LDHA. Taken together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
HostingRepository	PRIDE
AnnounceDate	2021-08-05
AnnouncementXML	Submission_2021-08-05_02:26:51.687.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mehdi Mollapour
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	5800 TOF/TOF

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-06 22:34:56	ID requested
⏵ 1	2021-08-05 02:26:52	announced

Dataset with its publication pending

submitter keyword: FLCN LDHA Glycolysis

Mehdi Mollapour
contact affiliation	Department of Urology, 2 Department of Biochemistry and Molecular Biology, 3 Upstate Cancer Center, 4 College of Medicine SUNY Upstate Medical University Syracuse, NY, USA
contact email	mollapom@upstate.edu
lab head
Mehdi Mollapour
contact affiliation	SUNY Upstate Medical University
contact email	mollapom@upstate.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018410
     1. Label: PRIDE project
     2. Name: The Tumor Suppressor FLCN Regulates Glycolysis by Specifically Binding and Inhibiting Lactate Dehydrogenase-A