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ING4 Loss in Prostate Cancer Progression

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Technical Report,23 Sep 2014,22 Sep 2015

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Van Andel Research Institute Grand Rapids

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The goal of this project is to identify specific differentiation events whose disruption by Myc and Pten leads to aggressive PCa. Our Aims are to 1 determine how ING4 controls prostate epithelial differentiation 2 determine how loss of ING4 impacts tumorigenesis and 3 determine how loss of ING4 in patients relates to tumor progression. We found the following 1 Notch3 is a target of Myc required for differentiation. 2 CREBATF1controls ING4 expression and differentiation, and the dynamics of CREBATF1 activation and its targets differ between normal and tumor cells. 3 Miz1 is an ING4 target required to suppress integrin 6 and 1 that is absent in tumor cells. 4 Erg negatively impacts differentiation, but only when expressed in the AR-positive cells. 5 Pten protein phosphatase activity sets the timing of differentiation, CREBATF1 activation, and induction of ING4. We identified targets of Myc, ING4, and CREB that can be used to screen human tissues proposed in Aim 3. We have met almost all of our first year objectives and extended into some of next years objectives.

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