Prenyl diphosphate synthase subunit 2 (PDSS2) is the first key enzyme in the CoQ
10 biosynthesis pathway, and contributes to various metabolic and nephritic diseases. It has been reported that
PDSS2 is downregulated in several types of tumors and acts as a potential tumor suppressor gene to inhibit the proliferation and migration of cancer cells. However, the regulatory mechanism of
PDSS2 expression remains elusive. In the present study, we first identified and characterized the
PDSS2 promoter region. We established four different luciferase reporter constructs which mainly cover the 2 kb region upstream of the
PDSS2 gene transcription initiation site. Series luciferase reporter assay demonstrated that all four constructs have prominent promoter activity, and the core promoter of
PDSS2 is mainly located within the 202 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the
PDSS2 promoter contains binding sites for canonical transcription factors such as Sp1 and GATA-1. Overexpression of
Sp1 significantly inhibited
PDSS2 promoter activity, as well as its endogenous expression, at both mRNA and protein levels in lung cancer cells. Site-directed mutagenesis assay further confirmed that the Sp1 binding sites are essential for proximal prompter activity of
PDSS2. Consistently, a selective Sp1 inhibitor, mithramycin A, treatment repressed the
PDSS2 promoter activity, as well as its endogenous expression. Chromatin immunoprecipitation (ChIP) assay revealed that Sp1 binds to the
PDSS2 promoter in vivo. Of note, the expression of
Sp1 and
PDSS2 are negatively correlated, and higher
Sp1 expression with low
PDSS2 expression is significantly associated with poor prognosis in lung cancer. Taken together, our results strongly suggest the essential role of Sp1 in maintaining the basic constitutive expression of
PDSS2, and the pathogenic implication of Sp1-mediated
PDSS2 transcriptional repression in lung cancer cells.
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