PXD054882

PXD054882 is an original dataset announced via ProteomeXchange.

Title	Sorafenib induces muscle wasting by disrupting the activity of distinct chromatin regulators
Description	n cancer treatment regimens using chemotherapy, adverse effects can outweigh the benefits. Various chemotherapeutic drugs are linked to skeletal muscle wasting, drastically reducing the chance of survivability of cancer patients. Insights into the molecular basis of chemotherapy-induced cachexia is an unmet need to improve the treatment strategies. Here, we investigated tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents for their effects on muscle function. Sorafenib (Sor), but not Nilotinib (Nilo) and Imatinib (Ima), triggered cachexia. Our system-wide analyses revealed that Sor alters the global transcription program and proteostasis in muscle cells. Mechanistically, Sor impeded chromatin association of SET1/MLL histone methyltransferase on distinct muscle-specific genes. Thus, it reduced H3K4 methylation and rendered the chromatin transcriptionally incompetent, as characterized by diminished association of RNA polymerase II. This transcriptional reorientation resulted in disruption of sarcomere organization, drastically perturbed calcium homeostasis, and mitochondrial respiration in muscle cells. Consequently, Sor-treatment severely compromised the contractile ability of muscle cells. Collectively, we identified an unanticipated epigenetic process affected by Sor that led to cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced muscle wasting and improve treatment outcomes.
HostingRepository	PRIDE
AnnounceDate	2025-05-07
AnnouncementXML	Submission_2025-05-07_00:08:28.234.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andreas Picjh
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	S-carboxamidoethyl-L-cysteine; monohydroxylated residue; deamidated residue
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-14 04:14:27	ID requested
⏵ 1	2025-05-07 00:08:29	announced

Khan B, Lanzuolo C, Rosti V, Santarelli P, Pich A, Kraft T, Amrute-Nayak M, Nayak A, Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes. iScience, 27(10):110913(2024) [pubmed]

10.1016/j.isci.2024.110913;

submitter keyword: mitochondrial respiration, sarcomere organization, muscle contraction, cachexia, sorafenib,Tyrosine kinase inhibitors

Andreas Pich
contact affiliation	Core Facility Proteomics Hannover Medical School Carl-Neuberg-Str. 1 30625 Hannover Germany
contact email	pich.andreas@mh-hannover.de
lab head
Andreas Picjh
contact affiliation	Hannover Medical School Core Facility Proteomics
contact email	pich.andreas@mh-hannover.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054882
     1. Label: PRIDE project
     2. Name: Sorafenib induces muscle wasting by disrupting the activity of distinct chromatin regulators