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Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation

Oncogene volume 40, pages 3260–3272 (2021)Cite this article

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Abstract

The molecular mechanisms of luminal cell differentiation are not understood well enough to determine how differentiation goes awry during oncogenesis. Using RNA-Seq analysis, we discovered that CREB1 plays a central role in maintaining new luminal cell survival and that oncogenesis dramatically changes the CREB1-induced transcriptome. CREB1 is active in luminal cells, but not basal cells. We identified ING4 and its E3 ligase, JFK, as CREB1 transcriptional targets in luminal cells. During luminal cell differentiation, transient induction of ING4 expression is followed by a peak in CREB1 activity, while JFK increases concomitantly with CREB1 activation. Transient expression of ING4 is required for luminal cell induction; however, failure to properly down-regulate ING4 leads to luminal cell death. Consequently, blocking CREB1 increased ING4 expression, suppressed JFK, and led to luminal cell death. Thus, CREB1 is responsible for the suppression of ING4 required for luminal cell survival and maintenance. Oncogenic transformation by suppressing PTEN resulted in constitutive activation of CREB1. However, the tumor cells could no longer fully differentiate into luminal cells, failed to express ING4, and displayed a unique CREB1 transcriptome. Blocking CREB1 in tumorigenic cells suppressed tumor growth in vivo, rescued ING4 expression, and restored luminal cell formation, but ultimately induced luminal cell death. IHC of primary prostate tumors demonstrated a strong correlation between loss of ING4 and loss of PTEN. This is the first study to define a molecular mechanism whereby oncogenic loss of PTEN, leading to aberrant CREB1 activation, suppresses ING4 expression causing disruption of luminal cell differentiation.

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Fig. 1: CREB1 gene signature in differentiating luminal cells.
Fig. 2: CREB1 is required for luminal cell survival.
Fig. 3: CREB1 limits ING4 expression during differentiation.
Fig. 4: ING4 E3 Ligase JFK is a target of CREB1 and ING4.
Fig. 5: CREB1 targets different genes upon oncogenic transformation.
Fig. 6: ING4 loss is associated with PTEN loss.
Fig. 7: CREB1 suppresses luminal cell differentiation in tumorigenic EMP cells.

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Acknowledgements

We wish to thank the bioinformatics and pathology cores at the Van Andel Institute and University of Arizona (BBSR, TACMSR), and the experimental mouse core (EMSR) at University of Arizona for all their help with this study. These studies were supported by funding from the Department of Defense, W81XWH-14-1-0479 (MJW, PLB, CKM) and W81XWH-17-1-0570 (SBF, KB, LT, CKM) and funding from the Van Andel Research Institute. Cores at the University of Arizona were supported by funds from NIH/NCI P30 CA023074.

Funding

MJW, PLB, KB, SBF, TL, SSG CKM – 2 grants from DOD; GH, MW – VAI.

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Authors and Affiliations

  1. Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA

    M. J. Watson, P. L. Berger, G. Hostetter, M. Winn & C. K. Miranti

  2. Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    K. Banerjee, S. B. Frank, L. Tang, S. S. Ganguly & C. K. Miranti

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Watson, M.J., Berger, P.L., Banerjee, K. et al. Aberrant CREB1 activation in prostate cancer disrupts normal prostate luminal cell differentiation. Oncogene 40, 3260–3272 (2021). https://doi.org/10.1038/s41388-021-01772-y

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