Mitochondrial Function of CKS2 Oncoprotein Links Oxidative Phosphorylation with Cell Division in Chemoradioresistant Cervical Cancer.
Biomarkers, Tumor
CDC2-CDC28 Kinases
/ genetics
Carrier Proteins
/ genetics
Cell Cycle
/ genetics
Cell Cycle Proteins
/ genetics
Cell Division
/ genetics
Cell Line, Tumor
DNA Replication
/ genetics
Drug Resistance, Neoplasm
/ genetics
Female
Fluorescent Antibody Technique
Gene Expression
Gene Expression Profiling
Humans
Immunohistochemistry
Mitochondria
/ genetics
Oncogene Proteins
/ genetics
Oxidative Phosphorylation
Prognosis
Radiation Tolerance
/ genetics
Uterine Cervical Neoplasms
/ metabolism
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
23
11
2018
revised:
04
01
2019
accepted:
08
01
2019
pubmed:
12
3
2019
medline:
5
6
2019
entrez:
12
3
2019
Statut:
ppublish
Résumé
CDK regulatory subunit 2 (CKS2) has a nuclear function that promotes cell division and is a candidate biomarker of chemoradioresistance in cervical cancer. The underlying mechanisms are, however, not completely understood. We investigated whether CKS2 also has a mitochondrial function that augments tumor aggressiveness. Based on global gene expression data of two cervical cancer cohorts of 150 and 135 patients, we identified a set of genes correlated with CKS2 expression. Gene set enrichment analysis showed enrichment of mitochondrial cellular compartments, and the hallmarks oxidative phosphorylation (OXPHOS) and targets of the MYC oncogene in the gene set. By in situ proximity ligation assay, we showed that CKS2 formed complex with the positively correlated MYC target, mitochondrial single-stranded DNA binding protein SSBP1, in the mitochondrion of cervix tumor samples and HeLa and SiHa cervical cancer cell lines, indicating a role in mitochondrial DNA (mtDNA) replication and thereby OXPHOS. CDK1 was found to be part of the complex. Flow cytometry analyses of HeLa cells showed cell cycle regulation of the CKS2-SSBP1 complex consistent with mtDNA replication activity. Moreover, repression of mtDNA replication and OXPHOS by acute hypoxia decreased CKS2-SSBP1 complex abundance and expression of MYC targets. By immunohistochemistry, cytoplasmic CKS2 expression was found to add to the prognostic impact of nuclear CKS2 expression in patients, suggesting that the mitochondrial function promotes tumor aggressiveness. Our study uncovers a novel link between regulation of cell division by nuclear pathways and OXPHOS in the mitochondrion that involves CKS2 and promotes chemoradioresistance of cervical cancer.
Identifiants
pubmed: 30856376
pii: S1476-5586(18)30636-5
doi: 10.1016/j.neo.2019.01.002
pmc: PMC6411633
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Carrier Proteins
0
Cell Cycle Proteins
0
Oncogene Proteins
0
CDC2-CDC28 Kinases
EC 2.7.11.22
CKS2 protein, human
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
353-362Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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