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 journalArticle

66 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 (US)
Pages (from-to)908-916
Number of pages9
JournalGenes and Cancer
Volume1
Issue number9
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Pharmaceutical Preparations
Neoplasms
Drug Resistance
Side-Population Cells
Cell Line
Polymerase Chain Reaction
SCID Mice
Neoplastic Stem Cells
Nucleic Acid Regulatory Sequences
Microarray Analysis
Embryonic Stem Cells
Methylation
Small Interfering RNA
Transcriptional Activation
Genes
Culture Media
Carcinogenesis
Transcription Factors
Up-Regulation

Keywords

  • Drug resistance
  • OCT4
  • POU5F1
  • Prostate cancer

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Linn, D. E., Yang, X., Sun, F., Xie, Y., Chen, H., Jiang, R., ... Qiu, Y. (2010). A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells. Genes and Cancer, 1(9), 908-916. https://doi.org/10.1177/1947601910388271

A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells. / Linn, Douglas E.; Yang, Xi; Sun, Feng; Xie, Yingqiu; Chen, Hege; Jiang, Richeng; Chen, Hegang; Chumsri, Saranya; Burger, Angelika M.; Qiu, Yun.

In: Genes and Cancer, Vol. 1, No. 9, 2010, p. 908-916.

Research output: Contribution to journalArticle

Linn, DE, Yang, X, Sun, F, Xie, Y, Chen, H, Jiang, R, Chen, H, Chumsri, S, Burger, AM & Qiu, Y 2010, 'A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells', Genes and Cancer, vol. 1, no. 9, pp. 908-916. https://doi.org/10.1177/1947601910388271
Linn, Douglas E. ; Yang, Xi ; Sun, Feng ; Xie, Yingqiu ; Chen, Hege ; Jiang, Richeng ; Chen, Hegang ; Chumsri, Saranya ; Burger, Angelika M. ; Qiu, Yun. / A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells. In: Genes and Cancer. 2010 ; Vol. 1, No. 9. pp. 908-916.
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