PXD027480

PXD027480 is an original dataset announced via ProteomeXchange.

Title	The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma
Description	Deubiquitylases (DUBs) remove ubiquitin from proteins. In the context of cancer, their inhibition can induce the degradation of oncoproteins, that may otherwise be “undruggable”. Multiple myeloma (MM) is the second most common hematological malignancy with poor outcome and high sensitivity towards ubiquitin-proteasome-system (UPS) inhibitory therapies. However, the role of DUBs in MM pathophysiology and therapy has remained elusive. Starting from genetic screening for DUB dependencies in MM, we here identify OTUD6B as a central vulnerability in MM that drives the G1/S cell cycle transition by means of deubiquitylating and stabilizing LIN28B subsequent to LIN28B phosphorylation. LIN28B regulates miRNA biogenesis and exerts high expression in embryonic stem cells that becomes re-established in certain tumors, including MM. Binding of LIN28B at G1/S activates OTUD6B, which otherwise remains in a catalytically inactive state. As a consequence, stabilized LIN28B drives MYC expression via inhibition of let7 microRNAs, which in turn allows for a rapid transition of MM cells from G1 to S phase. Analyses of primary MM patient samples reveal a positive correlation of OTUDB6B expression with poor outcome, high MYC expression and MYC target gene induction, suggesting that high MYC levels in MM result from an activation of the OTUD6B-LIN28B nexus. Together, we here specify phosphorylation and cell cycle-dependent substrate binding as a means by which OTUD6B becomes activated to drive the G1/S transition via the LIN28B-MYC axis and nominate OTUD6B and LIN28B as actionable vulnerabilities in MM.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_06:37:33.831.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jana Zecha
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-21 07:53:32	ID requested
1	2022-10-12 09:38:56	announced
⏵ 2	2023-11-14 06:37:34	announced	2023-11-14: Updated project metadata.

Paulmann C, Spallek R, Karpiuk O, Heider M, Sch, ä, ffer I, Zecha J, Klaeger S, Walzik M, Ö, llinger R, Engleitner T, Wirth M, Keller U, Kr, ö, nke J, Rudelius M, Kossatz S, Rad R, Kuster B, Bassermann F, The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma. EMBO J, 41(20):e110871(2022) [pubmed]

submitter keyword: BioID, human, FLAG-IP, Orbitrap, OTUD6B

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany
contact email	kuster@tum.de
lab head
Jana Zecha
contact affiliation	Technical University of Munich, Freising, Germany
contact email	jana.zecha@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027480
     1. Label: PRIDE project
     2. Name: The OTUD6B-LIN28B-MYC axis determines cell cycle progression in multiple myeloma