PXD045563-1

PXD045563 is an original dataset announced via ProteomeXchange.

Title	HERC5 alters mitochondrial energy metabolism pathways in NSCLC
Description	In 2020, lung cancer remains the most diagnosed entity among men and third most among women, causing approximately 1.8 million deaths worldwide with an estimated 31.5% of new cases in men and 14.6% in women, respectively (1). Moreover, metastasized non-small cell lung cancer (NSCLC) continues to be one of the cancer entities with the worst prognosis as well as disease-free and overall survival despite the recent introduction of immunotherapy, with the patients’ 5-year-survival rate ranging still only between 10-20% (1). The development of cancer and metastasis is considered a multi-step process in which many factors are the topic of ongoing investigation. Thus, the identification of novel markers and targets, which are involved in disease progression, is an essential step in improving the survival of lung cancer patients. Previously, we identified HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) gene as the main target gene on 4q (6). Loss of 4q has been associated with advanced disease stage and worse prognosis in several cancer entities including lung, colorectal, pancreatic, and hepatocellular cancer (2–5). We showed that in NSCLC, HERC5 downregulation via promoter hypermethylation leads to an increase in disseminated tumor cells (DTCs) and occurrence of brain metastases in NSCLC as well as poorer overall survival (OS) (6). In hepatocellular cancer, low mRNA expression levels of HERC5 could similarly be correlated with shorter OS, which led to immune evasion by indirectly increasing infiltration by regulatory T-cells (5). It was thus postulated that HERC5 might serve as a novel metastasis suppressor gene. Originally described in the context of innate immune responses, HERC5 is known to serve as the cellular main E3 ligase of ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) (7,8), thereby catalyzing the transfer of ISG15 onto target proteins – a process called ISGylation. ISGylation is not only an important primary defense mechanism against viruses and other pathogens (9,10), but also associated with various diseases such as immunodeficiencies, neurodegenerative disorders and different types of cancer (11–14). Lately, energy metabolism has been proven to have a strong influence on tumorigenesis and metastasization (15–17). Given the enhanced energy demand of highly proliferating cells, tumor cells can undergo a change in energy consumption mechanisms – such as the well-described Warburg-effect, leading to a switch between ATP production through glycolysis rather than oxidative phosphorylation (OXPHOS) (18). Despite the lower yield in ATP through glycolysis, malignant cells often prefer this pathway even in the presence of oxygen, leading to an increase in metabolic byproducts which are necessary for the elevated demand of metabolites required due to their high proliferation rates (15,16). Deregulation of ISG15 have been linked to dysfunctional mitochondria as well as altered OXPHOS activity (19–22). In this study, we aimed at further elucidating the potential metastasis suppressing role of HERC5 in NSCLC. We therefore assessed the malignant potential of HERC5 loss in in vitro and in vivo NSCLC models and could confirm its capacity to transform NSCLC cells both in vitro and in vivo into a more aggressive phenotype. We furthermore performed mass spectrometry analyses to identify the main pathways altered by differential HERC5 expression in modified NSCLC cell lines and could show that HERC5 has an influence on mitochondrial composition, and energy metabolism pathways such as OXPHOS, leading to better adaptation and survival under prolonged inhibition of oxidative phosphorylation.
HostingRepository	PRIDE
AnnounceDate	2024-05-24
AnnouncementXML	Submission_2024-05-24_01:05:31.114.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bente Siebels
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-21 07:06:04	ID requested
⏵ 1	2024-05-24 01:05:31	announced

Schneegans S, L, ö, ptien J, Mojzisch A, Loreth D, Kretz O, Raschdorf C, Hanssen A, Gocke A, Siebels B, Gunasekaran K, Ding Y, Oliveira-Ferrer L, Brylka L, Schinke T, Schl, ü, ter H, Paatero I, Vo, ß H, Werner S, Pantel K, Wikman H, HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis. J Exp Clin Cancer Res, 43(1):110(2024) [pubmed]

10.1186/s13046-024-03020-z;

submitter keyword: NSCLC, OXPHOS, cancer metabolism

Harriet Wikman
contact affiliation	Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
contact email	h.wikman@uke.de
lab head
Bente Siebels
contact affiliation	Section for Mass spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact email	b.siebels@uke.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045563
     1. Label: PRIDE project
     2. Name: HERC5 alters mitochondrial energy metabolism pathways in NSCLC