ISSN: 1837-9664Journal of Cancer
Global reach, higher impact
J Cancer 2023; 14(3):379-392. doi:10.7150/jca.79058 This issue Cite
Research Paper
SKA2-mediated transcriptional downregulation of the key enzyme of CoQ10 biosynthesis PDSS2 in lung cancer cells
1. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
2. Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
3. Department of Basic Medical Sciences, Taizhou University, Taizhou, Zhejiang 318000, China.
*These authors contributed equally to this work.
Abstract
Lung cancer is the leading cause of cancer-associated mortality worldwide. SKA2 is a novel cancer-associated gene that plays critical roles in both cell cycle and tumorigenesis including lung cancer. However, the molecular mechanisms underlying its implication in lung cancer remains elusive. In this study, we first analyzed the gene expression profiling after SKA2 knockdown, and identified several candidate downstream target genes of SKA2, including PDSS2, the first key enzyme in CoQ10 biosynthesis pathway. Further experiments verified that SKA2 remarkably repressed PDSS2 gene expression at both mRNA and protein levels. Luciferase reporter assay showed that SKA2 repressed PDSS2 promoter activity through its Sp1-binding sites. Co-immunoprecipitation assay demonstrated that SKA2 associated with Sp1. Functional analysis revealed that PDSS2 remarkably suppressed lung cancer cell growth and motility. Furthermore, SKA2-induced malignant features can be also significantly attenuated by PDSS2 overexpression. However, CoQ10 treatment showed no obvious effects on lung cancer cell growth and motility. Of note, PDSS2 mutants with no catalytic activity exhibited comparable inhibitory effects on the malignant features of lung cancer cells and could also abrogate SKA2-promoted malignant phenotypes in lung cancer cells, highly suggesting a non-enzymatic tumor-suppressing activity of PDSS2 in lung cancer cells. The levels of PDSS2 expression were significantly decreased in lung cancer samples, and lung cancer patients with high expression of SKA2 and low expression of PDSS2 displayed remarkable poor prognosis. Collectively, our results demonstrated that PDSS2 is a novel downstream target gene of SKA2 in lung cancer cells, and the SKA2-PDSS2 transcriptional regulatory axis functionally contributes to human lung cancer cell malignant phenotypes and prognosis.
Keywords: SKA2, PDSS2, transcription regulation, lung cancer
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