Date of Graduation

8-2016

Document Type

Dissertation (PhD)

Program Affiliation

Biomedical Sciences

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

WENLIANG LI, Ph.D.

Committee Member

ZHIQIANG AN, Ph.D.

Committee Member

QINGYUN (JIM) LIU, Ph.D.

Committee Member

XIAODONG CHENG, Ph.D.

Committee Member

MIKHAIL KOLONIN, Ph.D.

Committee Member

GUANGWEI DU, Ph.D.

Abstract

Prostate cancer is the second leading cause of cancer death among American men. The American Cancer Society estimates that 180,890 men will be will be diagnosed with prostate cancer in 2016 in the USA. (http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics). Androgen deprivation therapy (ADT) is the standard treatment for early stage prostate cancer. But most patients relapse with aggressive variants of prostate cancer, with survival time between 1-3 years. In order to develop cure for such aggressive variants of prostate cancer, our present understanding of the mechanisms underlying its progression needs to be advanced.

Recently, it has been found that activation of β-adrenergic signaling pathway leads to aggressive variants of prostate cancer. β-adrenergic signaling involves the activation of β-adrenergic receptors (ADRBs), eventually leading to increased activation of cAMP response element-binding protein (CREB). Downstream targets of CREB activation in neuroendocrine differentiation as well as in neoangiogenesis are largely unknown, indicating that the underlying mechanisms of β-adrenergic signaling in prostate cancer progression are far from completely understood. For instance, while the epigenetic regulation by histone deacetylases 2 (HDAC2) is necessary for stress to induce cardiac hypertrophy, its mechanism are unknown in cancer progression. Similarly, another regulator of β-adrenergic signaling, GRK3 was recently shown to be a new critical regulator of prostate cancer progressionand tumor angiogenesis. However, mechanisms of GRK3 in prostate cancer progression and its regulation by ADRB2 signaling remain unknown.

Our hypothesis is that GRK3 and HDAC2 are critical downstream effectors of β-adrenergic signaling-activated CREB in promoting prostate cancer progression. Here, we show that CREB directly activates GRK3 transcription by binding to its promoter and this up-regulation of GRK3 expression by ADRB2/CREB pathway is sufficient as well as necessary to induce the neuroendocrine differentiation of prostate cancer cells. We also show that downstream of chronic stress and ADRB2, CREB binds to HDAC2 promoter and activates its expression. HDAC2 further suppresses the expression of thrombospondin 1 (TSP1) in order to induce angiogenesis, thus acting as a mediator for the β-adrenergic signaling pathway.

Here, we have introduced two new pathways acting downstream of the ADRB2/CREB axis. We show that the CREB/GRK3 axis leads to neuroendocrine prostate cancer progression. We have introduced a new paradigm that β-adrenergic signaling and epigenetic gene expression regulation may be working synergistically resulting in cancer progression.

Keywords

Chronic Stress, beta-adrenergic signaling, HDAC2, TSP1, angiogenesis, cancer progression, GRK3, CREB, neuroendocrine prostate cancer