Targeting prostate cancer angiogenesis through metastasis‐associated protein 1 (MTA1)

Li, Kai; Wang, Jun; Ivanovic, Marina; Chung, Yeon Tae; Laskin, William B.; Schulze-Hoepfner, Frank T.; Mirochnik, Yelena; Satcher, Robert L.; Levenson, Anait S.

doi:10.1002/pros.21240

Cited by 81 publications

(127 citation statements)

References 54 publications

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“…Western blot analysis was carried out as described previously (Butt et al ., 2017; Dhar et al ., 2015a,b, 2016, 2017; Dias et al ., 2013a,b; Kai et al ., 2010, 2011; Li et al ., 2013). The antibodies used in this study are listed in Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous studies, we have identified metastasis‐associated protein 1 (MTA1) as a novel factor involved in ‘vicious cycle’ of prostate cancer cells interacting with bone cells, and hypothesized that MTA1 may play a specific role in prostate cancer bone metastasis (Kai et al ., 2011). Our following studies validated high MTA1 expression in advanced metastatic prostate cancer and bone lesions of patients with prostate cancer (Dias et al ., 2013a; Kai et al ., 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Our following studies validated high MTA1 expression in advanced metastatic prostate cancer and bone lesions of patients with prostate cancer (Dias et al ., 2013a; Kai et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of MTA1 has been reported in various cancers (Levenson et al ., 2014). We and others have demonstrated the correlation of MTA1 expression with clinicopathological measures of prostate cancer progression: high Gleason score, development of castrate‐resistant disease, recurrence, and bone metastasis (Dias et al ., 2013a; Hofer et al ., 2006; Kai et al ., 2011). We have extensively reported on the critical role of MTA1 and its signaling at all stages of prostate cancer development and progression (Levenson et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

“…We have extensively reported on the critical role of MTA1 and its signaling at all stages of prostate cancer development and progression (Levenson et al ., 2014). In addition to our initial demonstration of MTA1's functional role in vitro and in xenografts (Dhar et al ., 2015a; Kai et al ., 2010, 2011; Li et al ., 2013), we recently demonstrated that MTA1 overexpression promotes molecular changes associated with inflammation‐mediated cancer initiation, epithelial‐to‐mesenchymal transition (EMT), and cancer progression linked to cell metastatic potential and angiogenesis in a multistage transgenic model of prostate cancer that closely mimics human disease (Butt et al ., 2017; Dhar et al ., 2016, 2017). Altogether, MTA1 is increasingly being recognized as an important upstream multifunctional regulator that affects various cellular responses, including cell adhesion, migration, and invasion in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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MTA1 drives malignant progression and bone metastasis in prostate cancer

et al. 2018

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Prostate cancer often metastasizes to the bone, leading to morbidity and mortality. While metastasis‐associated protein 1 (MTA1) is highly overexpressed in metastatic tumors and bone metastatic lesions, its exact role in the development of metastasis is unknown. Here, we report the role of MTA1 in prostate cancer progression and bone metastasis in vitro and in vivo. We found that MTA1 silencing diminished formation of bone metastases and impaired tumor growth in intracardiac and subcutaneous prostate cancer xenografts, respectively. This was attributed to reduced colony formation, invasion, and migration capabilities of MTA1 knockdown cells. Mechanistic studies revealed that MTA1 silencing led to a significant decrease in the expression of cathepsin B (CTSB), a cysteine protease critical for bone metastasis, with an expected increase in the levels of E‐cadherin in both cells and xenograft tumors. Moreover, meta‐analysis of clinical samples indicated a positive correlation between MTA1 and CTSB. Together, these results demonstrate the critical role of MTA1 as an upstream regulator of CTSB‐mediated events associated with cell invasiveness and raise the possibility that targeting MTA1/CTSB signaling in the tumor may prevent the development of bone metastasis in prostate cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Our following studies validated high MTA1 expression in advanced metastatic prostate cancer and bone lesions of patients with prostate cancer (Dias et al ., 2013a; Kai et al ., 2011). …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MTA1 drives malignant progression and bone metastasis in prostate cancer

et al. 2018

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MTA1‐activated Epi‐microRNA‐22 regulates E‐cadherin and prostate cancer invasiveness

et al. 2017

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We have previously shown that metastasis-associated protein 1 (MTA1), a chromatin remodeler, plays an important role in prostate cancer invasiveness, likely through regulation of epithelial-to-mesenchymal transition. Here, we identified miR-22 as an epigenetic-microRNA (Epi-miR) directly induced by MTA1 and predicted to target E-cadherin. Loss-of-function and overexpression studies of MTA1 reinforced its regulatory role in miR-22 expression. MiR-22 directly targets the 3'-untranslated region of E-cadherin, and ectopic overexpression of miR-22 diminishes E-cadherin expression. Overexpression of miR-22 in prostate cancer cells promotes cell invasiveness and migration. Meta-analysis of patient tumor samples indicates a positive correlation between MTA1 and miR-22, supporting their inhibitory effect on E-cadherin expression. Our findings implicate the MTA1/Epi-miR-22/E-cadherin axis as a new epigenetic signaling pathway that promotes tumor invasion in prostate cancer.

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Targeting MTA1/HIF‐1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

et al. 2017

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The metastasis‐associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression‐related epigenetic regulator, which is overexpressed in hormone‐refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate‐specific Pten‐null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate‐specific Pten‐null mouse model (Pb‐Cre +; Pten f/f; Rosa26 Luc/+) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1‐associated proangiogenic factors HIF‐1α, VEGF, and IL‐1β leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF‐1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF‐1α tumor‐promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1‐targeted therapies in PCa.

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Targeting prostate cancer angiogenesis through metastasis‐associated protein 1 (MTA1)

Abstract: MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa.

Cited by 81 publications

References 54 publications

MTA1 drives malignant progression and bone metastasis in prostate cancer

MTA1 drives malignant progression and bone metastasis in prostate cancer

MTA1‐activated Epi‐microRNA‐22 regulates E‐cadherin and prostate cancer invasiveness

Targeting MTA1/HIF‐1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

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