title: Overexpression of PGC‑1α enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein.
abstract: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC‑1α), a coactivator interacting with multiple transcription factors, regulates several metabolic processes. Although recent studies have focused on the role of PGC‑1α in cancer, the underlying molecular mechanism has not been clarified. Therefore, we evaluated the role of PGC‑1α in cell proliferation and tumorigenesis using human embryonic kidney (HEK)293 cells and colorectal cancer cells. We established stable HEK293 cell lines expressing PGC‑1α and examined cell proliferation, anchorage-independent growth, and oncogenic potential compared to parental HEK293 cells. To identify the molecular PGC‑1α targets for increased cell proliferation and tumorigenesis, the GeneFishing™ DEG (differentially expressed genes) screening system was used. Western blot analysis and immunofluorescence staining were performed for a regulated gene product to confirm the results. Forced expression of PGC‑1α in HEK293 cells promoted cell proliferation and anchorage-independent growth in soft agar. In addition, HEK293 cells that highly expressed PGC‑1α showed enhanced tumor formation when subcutaneously injected into the bilateral flanks of immunodeficient mice. The results of the GeneFishing DEG screening system identified one upregulated gene (Acyl-CoA binding protein; ACBP). Real-time RT-PCR, western blot analysis, and immunofluorescence staining showed that ACBP was markedly increased in HEK293 cells stably overexpressing PGC‑1α (PGC‑1α-HEK293 cells) compared to those expressing an empty vector. In PGC‑1α, ACBP, and specificity protein 1 (Sp1) siRNA knockdown experiments in PGC‑1α-HEK293 and SNU-C4 cells, we also observed inhibition of cell proliferation, reduced expression of antioxidant enzymes, and increased H2O2-induced reactive oxygen species production and apoptosis. These findings suggest that PGC‑1α may promote cell proliferation and tumorigenesis through upregulation of ACBP. We provide evidence that increased Sp1 expression might contribute to enhanced ACBP expression by PGC‑1α. The current results also suggest that PGC‑1α, whose expression is related to enhanced cell proliferation and tumorigenesis, may be a good candidate molecular target for cancer therapy.
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Yun
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Eun-Seon
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry, Dong-A University College of Medicine, Busan, Republic of Korea.
authors.forename: Joo-In
authors.initials: JI
authors.lastname: Park
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D026261:Diazepam Binding Inhibitor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016329:Sp1 Transcription Factor / Q000235:genetics*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation / Q000235:genetics
chemical_list: D026261:Diazepam Binding Inhibitor; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D014157:Transcription Factors