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Carcinogenesis. 2018 May 28;39(6):838-849. doi: 10.1093/carcin/bgy054.

KRIBB53 binds to OCT4 and enhances its degradation through the proteasome, causing apoptotic cell death of OCT4-positive testicular germ cell tumors.

Jung J1,2, Kim Y1,2, Song J2,3, Yoon YJ4, Kim DE1,2, Kim JA1,2, Jin Y2,3, Lee YJ4, Kim S3, Kwon BM2,4, Han DC1,2.

Author information

1
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea.
2
University of Science and Technology in Korea, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea.
3
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea.
4
Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon, Korea.

Abstract

We hypothesized that octamer-binding transcription factor 4 (OCT4) inhibition would have therapeutic benefits in testicular germ cell tumors (TGCT). To identify inhibitors of OCT4, a chemical library was screened using a luciferase reporter system under the control of an OCT4 response element. A compound named KRIBB53 was identified based on its blocking of OCT4-dependent luciferase activation. When NCCIT cells were exposed to KRIBB53, the expression levels of OCT4 target genes, such as NANOG and USP44, were inhibited with an IC50 of 13 and 15 μM, respectively. In addition, the levels of OCT4 were decreased by exposing NCCIT cells to KRIBB53, and pretreating the cells with the proteasomal inhibitor MG132 reversed the KRIBB53-induced OCT4 degradation. Biotinyl-KRIBB53 was synthesized and showed comparable activity to KRIBB53 in OCT4 downregulation. Using affinity chromatography assay, KRIBB53 was shown to associate with OCT4 in vitro. Furthermore, the drug affinity responsive target stability (DARTS) assay confirmed unmodified KRIBB53 binding to OCT4. KRIBB53 selectively inhibited proliferation of TGCT cells such as NCCIT and Tera-1 cells but not that of immortalized normal cells. Finally, the administration of KRIBB53 at 30 mg/kg reduced tumor volumes by 77% in the mice xenografted with NCCIT cells relative to their vehicle-treated counterparts. Immunoblotting assays showed that expression of OCT4 was lower in KRIBB53-treated tumor tissues than in control tissues. We provide the first report, to our knowledge, of an OCT4 inhibitor that binds to OCT4 and induces its degradation.

PMID:
29668859
DOI:
10.1093/carcin/bgy054
[Indexed for MEDLINE]

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