ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer

Wang, Yan; Dan, Liangying; Li, Qianqian; Li, Lili; Zhong, Li-Ye; Shao, Bianfei; Yu, Fang; He, Sanxiu; Tian, Shaorong; He, Jin; Xiao, Qian; Putti, Thomas Choudary; He, Xueling; Feng, Yixiao; Lin, Yong; Xiang, Tingxiu

doi:10.1186/s13148-019-0785-z

Cited by 14 publications

(14 citation statements)

References 43 publications

(40 reference statements)

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“…TSGs are critical in the mediation of tumorigenesis 3 , 4 . Thus, identifying new TSGs and addressing unknown molecular events in BrCa is essential to characterizing carcinogenesis mechanisms, establishing novel prognostic biomarkers and even developing efficient therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

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Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Tan¹,

Sun²,

Liu³

et al. 2021

Theranostics

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103

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Rationale: Breast cancer (BrCa) is the most common cancer worldwide, and the 5-year relative survival rate has declined in patients diagnosed at stage IV. Advanced BrCa is considered as incurable, which still lack effective treatment strategies. Identifying and characterizing new tumor suppression genes is important to establish effective prognostic biomarkers or therapeutic targets for late-stage BrCa. Methods: RNA-seq was applied in BrCa tissues and normal breast tissues. Through analyzing differentially expressed genes, DRD2 was selected for further analysis. And expression and promoter methylation status of DRD2 were also determined. DRD2 functions were analyzed by various cell biology assays in vitro . Subcutaneous tumor model was used to explore DRD2 effects in vivo . A co-cultivated system was constructed to investigate interactions of DRD2 and macrophages in vitro . WB, IHC, IF, TUNEL, qRT-PCR, Co-IP, Antibody Array, and Mass Spectrum analysis were further applied to determine the detailed mechanism. Results: In BrCa, DRD2 was found to be downregulated due to promoter methylation. Higher expression of DRD2 positively correlated with longer survival times especially in HER2-positive patients. DRD2 also promoted BrCa cells sensitivity to Paclitaxel. Ectopic expression of DRD2 significantly inhibited BrCa tumorigenesis. DRD2 also induced apoptosis as well as necroptosis in vitro and in vivo . DRD2 restricted NF-κB signaling pathway activation through interacting with β-arrestin2, DDX5 and eEF1A2. Interestingly, DRD2 also regulated microenvironment as it facilitated M1 polarization of macrophages, and triggered GSDME-executed pyroptosis. Conclusion: Collectively, this study novelly manifests the role of DRD2 in suppressing BrCa tumorigenesis, predicting prognosis and treatment response. And this study further reveals the critical role of DRD2 in educating M1 macrophages, restricting NF-κB signaling pathway and triggering different processes of programmed cell death in BrCa. Taking together, those findings represent a predictive and therapeutic target for BrCa.

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Section: Discussionmentioning

confidence: 99%

“…Tumor suppression genes (TSGs) are critical for tumor progression, which are often downregulated and frequently silenced by DNA methylation in BrCa 3 , 4 . DNA methylation is the major epigenetic modification 5 .…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Tan¹,

Sun²,

Liu³

et al. 2021

Theranostics

Self Cite

103

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“…To determinate the mechanism underlying the effects of miR-25-5p in OSCC cells, the candidate target genes of miR-25-5p were predicted using the TargetScanHuman7.2 ( ) and miRWalk ( ). Among these target genes of miR-25-5p, KLK9, WNT3A, FGF18, SRSF4, FIBP, SOX12, TGFBI, and NEDD9 have been reported to participate in the development human cancers ( 42 – 49 ). Thus, we selected these genes for further investigation.…”

Section: Resultsmentioning

confidence: 99%

“…There are lots of target genes of miR-25-5p according to the results of quick search on TargetScan databases. Among these target genes, KLK9, WNT3A, FGF18, FIBP, SOX12, TGFBI, and NEDD9 have been reported to participate in the development of human cancers ( 42 – 49 ). The results of RT-qPCR indicated that among KLK9, WNT3A, FGF18, SRSF4, FIBP, SOX12, TGFBI, and NEDD9, the expression of NEDD9 was much higher in OSCC tissues than adjacent tissues.…”

Section: Discussionmentioning

confidence: 99%

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Melatonin Inhibits the Progression of Oral Squamous Cell Carcinoma via Inducing miR-25-5p Expression by Directly Targeting NEDD9

Wang¹,

Tao

Mao

et al. 2020

Front. Oncol.

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Melatonin exerts anti-cancer roles in various types of cancers. However, to the best of our knowledge, its role in oral squamous cell carcinoma (OSCC) is unknown. The present study aimed to investigate the role of melatonin and its underlying mechanism in OSCC. MTT, colony formation, wound healing, and transwell invasion assays proved that melatonin played anti-tumor effects in OSCC cells by inhibiting cell viability, proliferation, migration, and invasion in a concentration-dependent manner. The RT-qPCR analysis showed that miR-25-5p was significantly upregulated after melatonin treatment. Further, miR-25-5p might be involved in melatonin-induced inhibitory effects on the biological behavior of OSCC. The expression of miR-25-5p was decreased in tumor tissues and OSCC cells detected by RT-qPCR. MTT assay, colony formation assay, and TUNEL staining indicated miR-25-5p overexpression inhibited OSCC cell viability, proliferation, and induced OSCC cell apoptosis. Furthermore, wound healing, transwell invasion assay, and animal experiments suggested that miR-25-5p might exert suppressive effects on the migration, invasion, and tumor formation of OSCC cells, while miR-25-5p knockdown exhibited the opposite effects in OSCC cells. Bioinformatics analysis, western blot analysis, and luciferase reporter assay suggested that neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) was proved to be a putative target for miR-25-5p. The role of NEDD9 in inhibiting OSCC cell proliferation, invasion, and migration was verified with NEDD9 siRNA transfection. Thus, melatonin exerted anti-proliferative, anti-invasive, and anti-migrative effects on OSCC via miR-25-5p/NEDD9 pathway. Melatonin could be applied as a potential novel drug on treating OSCC.

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Human artificial chromosome carrying 3p21.3-p22.2 region suppresses hTERT transcription in oral cancer cells

2023

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Telomerase is a ribonucleoprotein ribonucleic enzyme that elongates telomere repeat sequences at the ends of chromosomes and contributes to cellular immortalization. The catalytic component of telomerase, human telomerase reverse transcriptase (hTERT), has been observed to be reactivated in immortalized cells. Notably, most cancer cells have been found to have active hTERT mRNA transcription, resulting in continuous cell division, which is crucial for malignant transformation. Therefore, discovering mechanisms underlying the regulation of hTERT transcription is an attractive target for cancer-specific treatments.Loss of heterozygosity (LOH) of chromosome 3p21.3 has been frequently observed in human oral squamous cell carcinoma (OSCC). Moreover, we previously reported that HSC3 OSCC microcell hybrid clones with an introduced human chromosome 3 (HSC3#3) showed inhibition of hTERT transcription compared with the parental HSC3 cells. This study examined whether hTERT transcription regulators are present in the 3p21.3 region. We constructed a human artificial chromosome (HAC) vector (3p21.3-HAC) with only the 3p21.3-p22.2 region and performed functional analysis using the 3p21.3-HAC. HSC3 microcell hybrid clones with an introduced 3p21.3-HAC exhibited significant suppression of hTERT transcription, similar to the microcell hybrid clones with an intact chromosome 3. In contrast, HSC3 clones with truncated chromosome 3 with deletion of the 3p21.3 region (3delp21.3) showed no effect on hTERT expression levels. These results provide direct evidence that hTERT suppressor gene(s) were retained in the 3p21.3 region, suggesting that the presence of regulatory factors that control telomerase enzyme activity may be involved in the development of OSCC.

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ZMYND10, an epigenetically regulated tumor suppressor, exerts tumor-suppressive functions via miR145-5p/NEDD9 axis in breast cancer

Cited by 14 publications

References 43 publications

Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer

Melatonin Inhibits the Progression of Oral Squamous Cell Carcinoma via Inducing miR-25-5p Expression by Directly Targeting NEDD9

Human artificial chromosome carrying 3p21.3-p22.2 region suppresses hTERT transcription in oral cancer cells

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