Mitochondrial Function of CKS2 Oncoprotein Links Oxidative Phosphorylation with Cell Division in Chemoradioresistant
Marte Jonsson1, Christina Sæten Fjeldbo1, Ruth Holm2
1Department of Radiation Biology, Oslo University Hospital, Oslo, Norway.
Abstract:
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.
Insights
CDK regulatory subunit 2 (CKS2) has a novel mitochondrial role in cervical cancer, impacting oxidative phosphorylation and promoting tumor aggressiveness. This finding links nuclear cell division regulation to mitochondrial function, potentially explaining chemoradioresistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- CDK regulatory subunit 2 (CKS2) is known for its nuclear role in cell division and as a potential biomarker for cervical cancer chemoradioresistance.
- The precise mechanisms underlying CKS2's role in tumor progression, particularly beyond its nuclear function, remain incompletely understood.
Purpose of the Study:
- To investigate a potential mitochondrial function of CKS2 and its contribution to cervical cancer aggressiveness.
- To elucidate the molecular mechanisms linking CKS2's nuclear and mitochondrial activities in cervical cancer.
Main Methods:
- Analysis of global gene expression data from two cervical cancer patient cohorts (n=150 and n=135).
- Gene set enrichment analysis to identify pathways and cellular compartments associated with CKS2 expression.
- In situ proximity ligation assays to detect protein-protein interactions within tumor samples and cell lines.
- Flow cytometry to assess cell cycle regulation and mitochondrial DNA replication.
- Immunohistochemistry to evaluate CKS2 expression patterns in patient tissues.
Main Results:
- CKS2 expression correlated with genes involved in mitochondrial function, specifically oxidative phosphorylation (OXPHOS) and MYC targets.
- CKS2 forms a complex with mitochondrial single-stranded DNA binding protein 1 (SSBP1), a MYC target, within mitochondria, suggesting a role in mitochondrial DNA (mtDNA) replication and OXPHOS.
- This CKS2-SSBP1 complex formation is cell cycle-regulated and sensitive to hypoxia, which represses mtDNA replication and OXPHOS.
- Cytoplasmic CKS2 expression, in addition to nuclear expression, significantly impacts patient prognosis, indicating its role in tumor aggressiveness.
Conclusions:
- CKS2 possesses a novel mitochondrial function involving mtDNA replication and OXPHOS, alongside its known nuclear role in cell division.
- The interaction of CKS2 with SSBP1 in mitochondria links nuclear cell cycle regulation pathways with mitochondrial energy metabolism.
- This dual localization and function of CKS2 contribute to cervical cancer aggressiveness and may underlie its role in chemoradioresistance.
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