We propose that a novel oncogene ZBTB46 is associated with prostate cancer progression. The role of ZBTB46 in prostate cancer metastasis is largely unknown. We first identify that ZBTB46 is activated in advanced prostate cancer after androgen deprivation therapy (ADT). Mechanically, it is linked to regulation by miR-1 and modulation of a prostate tumor suppressor KLF4 expression. Our data suggest that the inactivated AR-miR-1 axis is positively connected to 表CM02 共 2 頁 第 2 頁 ZBTB46 induction. We hypothesize that the effect of androgen deprivation on AR inactivation may reduce the miR-1 expression and in turn mediates ZBTB46 expression, through a physical interaction between miR-1 and 3’UTR of ZBTB46. Treatment of the castration-resistance prostate cancer (CRPC) cells with an AR antagonist, MDV3100, resulted in increased ZBTB46 mRNA and protein expression. Our preliminary results suggest that the inactivated AR signaling is positively connected to ZBTB46 induction following ADT. Moreover, ectopic ZBTB46 exacerbated malignant phenotypes in prostate cancer cells, while modify ZBTB46 expression with a CRISPR/Cas9 system increased KLF4 expression. We will further identify whether the induction of ZBTB46 lead to increase prostate cancer progression that is linked to the dysregulated AR signaling pathway through inactivation of miR-1 and inversely associated with KLF4 expression. We anticipate that a novel molecular determinant of CRPC where the progression of the disease to a more invasive phenotype upon androgen deprivation. We will explore an oncogenic role for the ZBTB46 protein in tumor cell invasiveness and metastasis coupled to the regulation of KLF4 expression. We propose a model whereby ZBTB46 might function as a transcriptional factor to invert tumor suppressor role of KLF4, which constrain metastasis of prostate cancer. Alternatively, inhibition of AR may cause the activation of ZBTB46-promoting signaling pathway components that affect KLF4 expression and the cell biologic function. Therefore, in the treatment of metastatic prostate cancer cells, ZBTB46 may be also an important treatment target in addition to targeting AR signaling, the regulatory mechanisms of inactivating ZBTB46 will be further investigated. We will test this hypothesis in this three-year project, under the following specific aims: Specific Aim I: Investigate the molecular basis of ZBTB46 in regulation of prostate cancer progression and metastasis using both in vitro and in vivo models. Specific Aim II: Identify target substrates of ZBTB46 and determine regulatory mechanisms of ZBTB46 represses KLF4 in regulating prostate cancer metastasis. Specific Aim III: Determine the biological functions of ZBTB46 that inhibits KLF4 and its effect on androgen deprivation and on sensitivity to AR antagonist in prostate cancer.
|Effective start/end date||8/1/16 → 7/31/17|
- prostate cancer
- androgen deprivation therapy (ADT)
- androgen receptor (AR)
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