Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate

Liao, Chun-Peng; Lin, Ting Wei; Li, Pei-Chuan; Geary, Lauren; Chen, Kevin; Vaikari, Vijaya Pooja; Wu, Jason; Lin, Chi‐Hung; Gross, Mitchell E.; Shih, Jean C.

doi:10.1038/s41388-018-0325-x

Cited by 49 publications

(40 citation statements)

References 49 publications

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“…According to the study of Du et al, MAOA mediates a signaling pathway contributing to reactive oxygen species generation, through which cancer‐associated fibroblasts induce the epithelial‐mesenchymal transition, metastasis, and infiltration of prostate cancer 40 . Liao etal demonstrated that MAOA promoted prostate tumor cell proliferation by mediating AKT phosphorylation and that MAOA absence hampered the progression of prostate cancer 41 . In the present study, we found that decreased MAOA in HCC correlated with poor survival outcome.…”

Section: Discussionsupporting

confidence: 61%

The clinical value and potential molecular mechanism of the downregulation of MAOA in hepatocellular carcinoma tissues

Pang

et al. 2020

Cancer Medicine

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Background Hepatocellular carcinoma (HCC) remains one of the most common cancers worldwide and tends to be detected at an advanced stage. More effective biomarkers for HCC screening and prognosis assessment are needed and the mechanisms of HCC require further exploration. The role of MAOA in HCC has not been intensively investigated. Methods In‐house tissue microarrays, genechips, and RNAsequencing datasets were integrated to explore the expression status and the clinical value of MAOA in HCC. Immunohistochemical staining was utilized to determine MAOA protein expression. Intersection genes of MAOA related co‐expressed genes and differentially expressed genes were obtained to perform functional enrichment analyses. In vivo experiment was conducted to study the impact of traditional Chinese medicine nitidine chloride (NC) on MAOA in HCC. Results MAOA was downregulated and possessed an excellent discriminatory capability in HCC patients. Decreased MAOA correlated with poor prognosis in HCC patients. Downregulated MAOA protein was relevant to an advanced TNM stage in HCC patients. Co‐expressed genes that positively related to MAOA were clustered in chemical carcinogenesis, where CYP2E1 was identified as the hub gene. In vivo experiment showed that nitidine chloride significantly upregulated MAOA in a nude mouse HCC model. Conclusions A decreased MAOA level is not only correlated with aggressive behaviors in males but also serves as a promising biomarker for the diagnosis and prognosis of HCC patients. Moreover, MAOA may play a role in AFB1 toxic transformation through its synergistic action with co‐expressed genes, especially CYP3A4. MAOA also serves as a potential therapy target of NC in HCC patients.

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Section: Discussionsupporting

confidence: 61%

The clinical value and potential molecular mechanism of the downregulation of MAOA in hepatocellular carcinoma tissues

Pang

et al. 2020

Cancer Medicine

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“…MAOA is a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines and produces hydrogen peroxide. It has a well-established role in promoting aggressive prostate cancer cell growth, invasion, and metastasis [34–37]. MAOA is also reported as an AR target gene with an androgen response element (ARE) in its promoter [38].…”

Section: Resultsmentioning

confidence: 99%

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

Weber

Ruoff

Garabedian

2019

Preprint

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Androgen deprivation therapy (ADT) is a mainstay of prostate cancer treatment, given the dependence of prostate cells on androgen and the androgen receptor (AR). However, tumors become ADT-resistant, and there is a need to understand the mechanism. One possible mechanism is the upregulation of AR co-regulators, although only a handful have been definitively linked to disease. We previously identified the Mediator subunit MED19 as an AR co-regulator, and reported that MED19 depletion inhibits AR transcriptional activity and growth of androgen-insensitive LNCaP-abl cells. Therefore, we proposed that MED19 upregulation would promote AR activity and drive androgen-independent growth. Here, we show that stable overexpression of MED19 in androgen-dependent LNCaP cells promotes growth under conditions of androgen deprivation. To delineate the mechanism, we determined the MED19 and AR transcriptomes and cistromes in control and MED19 LNCaP cells. We also examined H3K27 acetylation genome-wide. MED19 overexpression selectively alters AR occupancy, H3K27 acetylation, and gene expression. Under conditions of androgen deprivation, genes regulated by MED19 and genomic sites occupied by MED19 and AR are enriched for ELK1, a transcription factor that binds the AR N-terminus to promote select AR-target gene expression. Strikingly, MED19 upregulates expression of monoamine oxidase A (MAOA), a factor that promotes prostate cancer growth. MAOA depletion reduces androgen-independent growth. MED19 and AR occupy the MAOA promoter, with MED19 overexpression enhancing AR occupancy and H3K27 acetylation. Furthermore, MED19 overexpression increases ELK1 occupancy at the MAOA promoter, and ELK1 depletion reduces MAOA expression and androgen-independent growth. This suggests that MED19 cooperates with ELK1 to regulate AR occupancy and H3K27 acetylation at MAOA, upregulating its expression and driving androgen independence in prostate cancer cells. This study provides important insight into the mechanisms of prostate cancer cell growth under low androgen, and underscores the importance of the MED19-MAOA axis in this process.Author summaryProstate cancer is one of the most common cancers worldwide, and androgen hormones are essential for prostate cancer growth. Androgens exert their effects through a protein called the androgen receptor (AR), which turns on and off genes that regulate prostate cancer growth. Powerful drugs that block AR action by lowering androgen levels – so-called androgen deprivation therapy - are used to treat prostate cancer patients, and these yield initial success in reducing tumor growth. However, over time, tumors circumvent androgen deprivation therapy and patients relapse; in many cases, this occurs because AR becomes re-activated. The factors responsible for re-activating AR and promoting growth under androgen deprivation are not well understood. Here, we demonstrate that a subunit of the Mediator transcriptional regulatory complex, called MED19, promotes growth of prostate cancer cells under low androgen conditions, mimicking the ability of tumors to grow under androgen deprivation in prostate cancer patients. MED19 promotes androgen-independent growth by working with a transcription factor that interacts with AR, called ELK1, to induce the expression of genes regulated by AR that promote prostate cancer growth. This study provides important insight into how prostate cancer cells can maintain growth under androgen deprivation through MED19.

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“…MAOB and MAOA have dramatic influence in the etiology of many neurological diseases . Moreover, Liao et al have proved that MAOA was involved in the development of adenocarcinoma. Prior study performed by Hussain et al and Tong et al elucidated the vital functions of MAOB on Alzheimer's disease and Parkinson's disease, but its function in some types of cancers such as endometrial carcinoma still remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…26,27 Growing reports disclosed that miR-522 is nor- MAOB and MAOA have dramatic influence in the etiology of many neurological diseases. 18,19 Moreover, Liao et al 30 have proved that MAOA was involved in the development of adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

miR‐522 facilitates the prosperities of endometrial carcinoma cells by directly binding to monoamine oxidase B

Zhang

Han

Zhang

et al. 2019

The Kaohsiung J of Med Scie

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It is well known that microRNAs (miRNAs) are crucial regulatory factors in tumorigenesis, as tumor suppressors or cancer‐promoting factors. However, the study of endometrial carcinoma relevance in miR‐522 is rare, indicating an undefined molecular mechanism for its role. Therefore, we performed this study to examine the role of miR‐522 on the biological behaviors of endometrial carcinoma. In this work, we found that miR‐522 was highly expressed in endometrial carcinoma and negatively regulated monoamine oxidase B (MAOB) expression. They also have the opposite effect on prognosis of endometrial carcinoma patients. More importantly, miR‐522 could decreased MAOB expression by binding to MAOB with a putative site, thereby promoting cell proliferation, migration, and invasion through in vitro functional analyses, including MTT assay, wound‐healing and transwell invasion experiments. Upregulation of MAOB rescued the impacts of miR‐522 mimic on cell behaviors. In conclusion, our observations demonstrated that miR‐522 accelerated the progression of endometrial carcinoma by inhibiting MAOB, which might lead to a novel therapeutic therapy for endometrial carcinoma.

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Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate

Cited by 49 publications

References 49 publications

The clinical value and potential molecular mechanism of the downregulation of MAOA in hepatocellular carcinoma tissues

The clinical value and potential molecular mechanism of the downregulation of MAOA in hepatocellular carcinoma tissues

MED19 alters AR occupancy and gene expression in prostate cancer cells, driving MAOA expression and growth under low androgen

miR‐522 facilitates the prosperities of endometrial carcinoma cells by directly binding to monoamine oxidase B

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