Abstract
Overexpression of the epigenetic modifier metastasis-associated protein 1 (MTA1) is associated with aggressive human prostate cancer. The purpose of this study was to determine MTA1- targeted chemopreventive and therapeutic efficacy of pterostilbene, a natural potent analog of resveratrol, in pre-clinical models of prostate cancer. Here, we show that high levels of MTA1 expression in Pten-loss prostate cooperate with key oncogenes, including c-Myc and Akt among others, to promote prostate cancer progression. Loss-of-function studies using human prostate cancer cells indicated direct involvement of MTA1 in inducing inflammation and epithelial-to-mesenchymal transition. Importantly, pharmacological inhibition of MTA1 by pterostilbene resulted in decreased proliferation and angiogenesis and increased apoptosis. This restrained prostatic intraepithelial neoplasia (PIN) formation in prostate-specific Pten heterozygous mice and reduced tumor development and progression in prostate-specific Pten-null mice. Our findings highlight MTA1 as a key upstream regulator of prostate tumorigenesis and cancer progression. More significantly, it offers pre-clinical proof for pterostilbene as a promising lead natural agent for MTA1-targeted chemopreventive and therapeutic strategy to curb prostate cancer.
Highlights
Besides the role of genetic alterations in cancer, substantial data support the idea that dietary/lifestyle factors affect cancer initiation, promotion and progression through epigenetic alterations [1, 2]
Based on our previous studies suggesting a possible inverse relationship between metastasis-associated protein 1 (MTA1) and PTEN [9, 17], we hypothesized that MTA1-targeted therapy would be effective for blocking Pten loss-driven prostate tumor growth and progression
We found that loss of only one Pten allele was sufficient to substantially increase MTA1 both at protein and mRNA levels (Figure 1A–1C), suggesting that MTA1 may be involved in the initiation stage of prostate cancer
Summary
Besides the role of genetic alterations in cancer, substantial data support the idea that dietary/lifestyle factors affect cancer initiation, promotion and progression through epigenetic alterations [1, 2]. In MTA1-expressing xenografts, we detected significantly higher tumor growth in PTEN-deficient LNCaP mice compared to the PTEN-expressing DU145-xenografts [9]. This observation coupled with our recent findings of PTEN’s deacetylation by MTA1 [17] prompted speculation that MTA1 might cooperate with PTEN loss for the establishment and progression of prostate cancer
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