A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells

Douglas E. Linn, Xi Yang, Feng Sun, Yingqiu Xie, Hege Chen, Richeng Jiang, Hegang Chen, Saranya Chumsri, Angelika M. Burger, Yun Qiu

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

Drug resistance remains a clinical challenge in cancer treatment due to poor understanding of underlying mechanisms. We have established several drug-resistant prostate cancer cell lines by long-term culture in medium containing chemotherapeutic drugs. These resistant lines displayed a significant increase in side population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1/Pgp. To uncover potential mechanisms underlying drug resistance, we performed microarray analysis to identify differentially expressed genes in 2 drug-resistant lines. We observed that POU5F1/OCT4, a transcription factor key to regulating pluripotency in embryonic stem cells, was upregulated in drug-resistant lines and accompanied by transcriptional activation of a set of its known target genes. Upregulation of OCT4 in drug-resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmation by Western blot and specific shRNA knockdown. Analysis of the regulatory region of POU5F1/OCT4 revealed a reduction of methylation in drug-resistant cell lines. Furthermore, these drug-resistant cells exhibited a significant increase in tumorigenicity in vivo. Subcutaneous inoculation of as few as 10 drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions, suggesting that these drug-resistant cells may be enriched for tumor-initiating cells. Knocking down OCT4 expression by specific shRNAs attenuated growth of drug-resistant cells. Our data suggest that OCT4 re-expression in cancer cells may play an important role in carcinogenesis and provide one possible mechanism by which cancer cells acquire/maintain a drug-resistant phenotype.

Original languageEnglish
Pages (from-to)908-916
Number of pages9
JournalGenes and Cancer
Volume1
Issue number9
DOIs
Publication statusPublished - 2010

Keywords

  • Drug resistance
  • OCT4
  • POU5F1
  • Prostate cancer

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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