The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer

He, Guoyang; Hu, Jingjing; Zhou, Lin; Zhu, Xiaohui; Xin, Sainan; Zhang, D; Lu, Gui-Feng; Liao, Wangjun; Ding, Yi; Li, Liang

doi:10.1038/bjc.2016.362

Cited by 44 publications

(48 citation statements)

References 53 publications

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“…Several studies have proposed that mRNAs and lncRNAs can regulate each other through their capacity to compete for miRNA binding [17,18]. In this study, for the first time, we reported that KCNQ1OT1 plays an important role in cataract formation.…”

Section: Discussionmentioning

confidence: 57%

Long Non-Coding RNA KCNQ1OT1 Promotes Cataractogenesis via miR-214 and Activation of the Caspase-1 Pathway

Jin

Hao²,

Shi

et al. 2017

Cell Physiol Biochem

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Background/Aims: KCNQ1OT1 regulates the expression of tissue-specific imprinted genes within the Kcnq1 domain. Imprinted genes are positive regulators of apoptosis, one of the forms of cell death related to cataract formation, and thus may provide novel therapeutic targets for cataract treatment. Here, we studied the role of non-coding RNAs(ncRNA) in cataract formation. Methods: Human lens epithelium cells (HLECs) were treated with H 2 O 2, and the expression of KCNQ1OT1 and miR-214 was detected by qRT-PCR. The expression of caspase-1 was detected using qRT-PCR, western blot and immunostaining. To confirm our findings in cell cultures, we analysed KCNQ1OT1, miR-214, and caspase-1 expression in lens anterior capsules of both cataract patients and normal controls by qRT-PCR and western blot analysis. Results: We found that the expression of KCNQ1OT1 was increased in both human cataract lens anterior capsular samples and SRA01/04 cell lines treated with H 2 O 2 . Knockdown of KCNQ1OT1 expression significantly suppressed H 2 O 2 -induced SRA01/04 cell pyroptosis in vitro, which is the critical step in cataract formation. The expression of microRNA-214 (miR-214) was also decreased in cataract lens anterior capsular tissues and H 2 O 2 -induced SRA01/04 cell lines. Knockdown of KCNQ1OT1 significantly increased the expression of miR-214. Conclusions: We demonstrated for the first time that caspase-1 is a functional downstream target of miR-214, and knockdown of KCNQ1OT1 reduced the expression of caspase-1. These results provide evidence that the KCNQ1OT1-miR-214-caspase-1 regulatory network is a novel mechanism for promoting cataract formation.

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Section: Discussionmentioning

confidence: 57%

Long Non-Coding RNA KCNQ1OT1 Promotes Cataractogenesis via miR-214 and Activation of the Caspase-1 Pathway

Jin

Hao²,

Shi

et al. 2017

Cell Physiol Biochem

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“…Previously, miR‐214 was reported to function as a tumor suppressor in colon cancer (11, 44, 45). miR‐214 inhibits colon cancer proliferation and migration via the suppression of ARL2 (44) and HMGA1 (45).…”

Section: Discussionmentioning

confidence: 99%

“…miR‐214 inhibits colon cancer proliferation and migration via the suppression of ARL2 (44) and HMGA1 (45). miR‐214/ MED19 axis suppresses tumor growth and metastasis in human CRC (11). In the present study, we found that miR‐214 levels were remarkably decreased in colon cancer.…”

Section: Discussionmentioning

confidence: 99%

“…These controversial results of miR‐22 in tumor progression suggest miR‐22 plays varied roles depending on cancer type. Regarding EMT, miR‐22 inhibits EMT by directly targeting MMP14 and SNAIL in gastric cancer and lung cancer (10, 11). However, in breast cancer, miR‐22 inhibits the demethylation of the miR‐200 promoter with the effect of EMT promotion (12).…”

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confidence: 99%

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miR‐22 and miR‐214 targeting BCL9L inhibit proliferation, metastasis, and epithelial‐mesenchymal transition by down‐regulating Wnt signaling in colon cancer

Sun

Liu²,

Lin

et al. 2019

FASEB j.

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The epithelial‐mesenchymal transition (EMT) is crucial for cancer progression. Evidence has shown that miR‐22 and miR‐214 play a key role in colon cancer progression; however, the underlying mechanism remains to be known. The effects of miR‐22 and miR‐214 on EMT are contradictory in different cancers, and whether miR‐22 and miR‐214 are involved in the colon cancer EMT process needs to be elucidated. In this study, we evaluated the exact role and the regulation mechanism of miR‐22 and miR‐214 in colon cancer. After transfection with miR‐22 expression vector, the cell proliferation and migration capacity of HCT116 and RKO cells were significantly suppressed. Also, E‐cadherin was increased and vimentin was decreased by miR‐22 overexpression. Similar effects were also observed after miR‐214 expression vector transfection. Dual‐lucif erase reporter confirmed that BCL9L is the target gene of both miR‐22 and miR‐214. Silencing of BCL9L inhibits cell proliferation and migration, and the expression of E‐cadherin and vimentin was also altered by BCL9L knockdown, which was consistent with miR‐22 or miR‐214 transfection. Furthermore, miR‐22 and miR‐214 inhibited tumor growth in nude mice. Moreover, although the association between BCL9L's lower expression and longer survival time was statistically nonsignificant, a trend existed; further studies in a larger cohort are needed. Collectively, these data suggest that miR‐22 and miR‐214 inhibit cell proliferation, migration, and EMT of colon cancer, most likely by targeting BCL9L.—Sun, R., Liu, Z., Han, L., Yang, Y., Wu, F., Jiang, Q., Zhang, H., Ma, R., Miao, J., He, K., Wang, X., Zhou, D., Huang, C. miR‐22 and miR‐214 targeting BCL9L inhibit proliferation, metastasis, and epithelial‐mesenchymal transition by down‐regulating Wnt signliang in colon cancer. FASEB J. 33, 5411–5424 (2019). http://www.fasebj.org

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“…Our study may also have implications for MED19 function in other cancers. For example, reduction of MED19 by siRNA has been reported to reduce the proliferation of certain breast, ovarian, cervical, and lung cancer cell lines, and increased abundance of MED19 protein is observed in tumors relative to benign tissue [55–62]. This suggests that MED19 functions with other transcription factors in other cell types to regulate gene expression and enhance cellular proliferation.…”

Section: Discussionmentioning

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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The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer

Cited by 44 publications

References 53 publications

Long Non-Coding RNA KCNQ1OT1 Promotes Cataractogenesis via miR-214 and Activation of the Caspase-1 Pathway

Long Non-Coding RNA KCNQ1OT1 Promotes Cataractogenesis via miR-214 and Activation of the Caspase-1 Pathway

miR‐22 and miR‐214 targeting BCL9L inhibit proliferation, metastasis, and epithelial‐mesenchymal transition by down‐regulating Wnt signaling in colon cancer

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

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