Abstract
Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
Highlights
Prostate cancer is the second most common cancer among men, with an estimated 1.3 million new cases worldwide in 2018 [1]
Motif hinge region of the Androgen receptor (AR) to mimic an acetylated phenotype of the receptor, the AR was mainly located in the nucleus even with androgen starvation [23], suggesting that these lysine residues are critical for AR activation
These findings are in accord with studies that have consistently identified that calmodulin-dependent kinase kinase 2 (CAMKK2) was overexpressed in human prostate tumor biopsies [9,43], highlighting the significance of AR-CAMKK2-AMPK signaling in mediating energy metabolism in prostate cancer
Summary
Prostate cancer is the second most common cancer among men, with an estimated 1.3 million new cases worldwide in 2018 [1]. Even though androgen deprivation therapy provides remission during the early stage of treatment, most patients eventually experience recurrence despite castrate levels of serum androgen [5] This incurable stage of prostate cancer is known as castrate-resistant prostate cancer and is associated with poor survival of only 9–13 months in those who develop metastases [6]. Sci. 2020, 21, x FOR PEER REVIEW [5] Alters anabolic and catabolic metabolism in prostate cancer cell lines [7,8,9,10].
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