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NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation

Oncogene volume 30, pages 3833–3845 (2011)Cite this article

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Abstract

Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to show oncogenic potential. We have recently reported that short-hairpin RNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using qRT–PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the −3.8-kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP+ PCa cells showed cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG-overexpressing cancer cell lines, including both PCa (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug resistance in MCF-7 cells, tumor regeneration in Du145 cells and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.

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Article 04 February 2021

Richard J. Rebello, Christoph Oing, … Robert G. Bristow

Abbreviations

AD:

androgen dependent

AI:

androgen independent

CE:

cloning efficiency

ChIP:

chromatin immunoprecipitation

CSC:

cancer stem cells

dox:

doxycycline

DP:

dorsal prostate

EMT:

epithelial mesenchymal transition

ESCs:

embryonic stem cells

HPCa:

human prostate cancer patient samples

NOD/SCID:

non-obese severe combined immunodeficient mice

PCa:

prostate cancer

qRT–PCR:

quantitative reverse-transcription polymerase chain reaction

s.c:

subcutaneous

SP:

side population

TSS:

transcription start site

UTR:

untranslated region

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Acknowledgements

We thank P Whitney for FACS, N Otto and the Histology Core for help in IHC analysis, J Moore for assistance in animal breeding and experiments, and other members of the Tang laboratory for support and discussions. This work was supported, in part, by grants from NIH (R01-ES015888, R21-ES015893, R21-CA150009), Department of Defense (W81XWH-07-1-0616, W81XWH-08-1-0472) and the Elsa Pardee Foundation (DGT), and by two Center Grants (CCSG-5 P30 CA016672-34 and ES007784). CR Jeter and C Liu were supported in part by fellowships from the AUA Foundation and DOD, respectively.

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Authors and Affiliations

  1. Department of Molecular Carcinogenesis, Science Park-Research Division, University of Texas MD Anderson Cancer Center, Smithville, TX, USA

    C R Jeter, B Liu, X Liu, X Chen, C Liu, T Calhoun-Davis, J Repass, J J Shen & D G Tang

  2. Department of Nutritional Sciences, The University of Texas, Austin, TX, USA

    X Liu

  3. Program in Molecular Carcinogenesis, The Graduate School for Biological Sciences, Houston, TX, USA

    X Chen, C Liu & D G Tang

  4. Max Planck Institute for Molecular Biomedicine, Munster, Germany

    H Zaehres

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Jeter, C., Liu, B., Liu, X. et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30, 3833–3845 (2011). https://doi.org/10.1038/onc.2011.114

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