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A reciprocal role of prostate cancer on stromal DNA damage

Oncogene volume 33, pages 4924–4931 (2014)Cite this article

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Abstract

DNA damage found in prostate cancer-associated fibroblasts (CAF) promotes tumor progression. In the absence of somatic mutations in CAF, epigenetic changes dictate how stromal coevolution is mediated in tumors. Seventy percent of prostate cancer patients lose expression of transforming growth factor-beta type II receptor (TGFBR2) in the stromal compartment (n=77, P-value=0.0001), similar to the rate of glutathione S-transferase P1 (GSTP1) silencing. Xenografting of human prostate cancer epithelia, LNCaP, resulted in the epigenetic Tgfbr2 silencing of host mouse prostatic fibroblasts. Stromal Tgfbr2 promoter hypermethylation, initiated by LNCaP cells, was found to be dependent on interleukin 6 expression, based on neutralizing antibody studies. We further found that pharmacologic and transgenic knockout of TGF-β responsiveness in prostatic fibroblasts induced Gstp1 promoter methylation. It is known that TGF-β promotes DNA stability, however, the mechanism is not well understood. Both prostatic human CAF and mouse transgenic knockout of Tgbr2 had elevated DNA methyltransferase I (DNMT1) activity and histone H3 lysine 9 trimethylation (H3K9me3) to suggest greater promoter methylation. Interestingly, the conditional knockout of Tgfbr2 in mouse prostatic fibroblasts, in modeling epigenetic silencing of Tgfbr2, had greater epigenetic gene silencing of multiple DNA damage repair and oxidative stress response genes, based on promoter methylation array analysis. Homologous gene silencing was validated by reverse transcriptase (RT)–PCR in mouse and human prostatic CAF. Not surprisingly, DNA damage repair gene silencing in the prostatic stromal cells corresponded with the presence of DNA damage. Restoring the expression of the epigenetically silenced genes in wild-type fibroblasts with radiation-induced DNA damage reduced tumor progression. Tumor progression was inhibited even when epigenetic silencing was reversed in the Tgfbr2-knockout prostatic fibroblasts. Taken together, fibroblastic epigenetic changes causative of DNA damage, initiated by association with cancer epithelia, is a dominant mediator of tumor progression over TGF-β responsiveness.

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Acknowledgements

The work was supported by R01CA108646 (to NAB) from the National Cancer Institute.

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Author notes

  1. J Banerjee

    Present address: 6Current address: Department of Biomedical and Diagnostic Sciences, University of Tennessee, Knoxville, TN, USA.,

  2. X Li

    Present address: 7Current address: Van Andel Institute, Grand Rapids, MI, USA.,

  3. J Banerjee and R Mishra: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Vanderbilt University, Nashville, TN, USA

    J Banerjee, X Li & R S Jackson II

  2. Department of Medicine, Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA

    R Mishra & N A Bhowmick

  3. Greater Los Angeles Veterans Administration, Los Angeles, CA, USA

    R S Jackson II & N A Bhowmick

  4. Department of Mechanical, Aerospace and Biomedical Engineering, University of Tennessee, Knoxville, TN, USA

    A Sharma

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Correspondence to N A Bhowmick.

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Banerjee, J., Mishra, R., Li, X. et al. A reciprocal role of prostate cancer on stromal DNA damage. Oncogene 33, 4924–4931 (2014). https://doi.org/10.1038/onc.2013.431

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