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Knockdown of SETDB1 inhibits breast cancer progression by miR-381-3p-related regulation.

ABSTRACT: BACKGROUND:SET domain bifurcated 1 (SETDB1) has been widely considered as an oncogene playing a critical role in many human cancers, including breast cancer. Nevertheless, the molecular mechanism by which SETDB1 regulates breast cancer tumorigenesis is still unknown. METHODS:qRT-PCR assay or western blot analysis was performed to assess the expression level of SETDB1 mRNA or protein, respectively. siSETDB1, pCMV6-XL5-SETDB1, miR-381-3p mimic, or miR-381-3p inhibitor was transfected into cells to regulate the expression of SETDB1 or miR-381-3p. MiRNA directly interacted with SETDB1 was verified by luciferase reporter assay and RNA immunoprecipitation. CCK-8 assay, colony formation assay, flow cytometric analysis, and transwell assay were used to detect the abilities of cell proliferation, cell cycle progression and migration, respectively. Animal model of xenograft tumor was used to observe the regulatory effect of SETDB1 on tumor growth in vivo. RESULTS:We verified that SETDB1 mRNA level was upregulated in breast cancer tissues and cell lines, and SETDB1 depletion led to a suppression of cell proliferation, cell cycle progression and migration in vitro, as well as tumor growth in vivo. SETDB1 was verified to be a target of miR-381-3p. Moreover, miR-381-3p overexpression suppressed cell proliferation, cell cycle progression and migration, whereas SETDB1 abated miR-381-3p-mediated regulatory function on breast cancer cells. CONCLUSIONS:This study revealed that SETDB1 knockdown might suppress breast cancer progression at least partly by miR-381-3p-related regulation, providing a novel prospect in breast cancer therapy.

SUBMITTER: Wu M

PROVIDER: S-EPMC6180515 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Knockdown of SETDB1 inhibits breast cancer progression by miR-381-3p-related regulation.

Wu Milu M Fan Baohua B Guo Qijing Q Li Yan Y Chen Rong R Lv Nannan N Diao Yinzhuo Y Luo Yushuang Y

Biological research 20181011 1

<h4>Background</h4>SET domain bifurcated 1 (SETDB1) has been widely considered as an oncogene playing a critical role in many human cancers, including breast cancer. Nevertheless, the molecular mechanism by which SETDB1 regulates breast cancer tumorigenesis is still unknown.<h4>Methods</h4>qRT-PCR assay or western blot analysis was performed to assess the expression level of SETDB1 mRNA or protein, respectively. siSETDB1, pCMV6-XL5-SETDB1, miR-381-3p mimic, or miR-381-3p inhibitor was transfecte ...[more]

PMID: 30309377

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Project description:BackgroundBreast cancer (BC) is one of the major malignancies worldwide. Circular ribonucleic acids (circRNAs) are a class of conserved ribonucleic acid (RNA) molecules that play important roles in various diseases. Recently, circRNAs have been suggested to have diagnostic value and may function as potential diagnostic biomarkers for BC. Previously, hsa_circ_0043278 was found to be downregulated in human BC. However, its role in human BC has not yet been identified.MethodsThe levels of hsa_circ_0043278 in BC cell lines were verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The overexpression vector and short hairpin RNA (shRNA) of hsa_circ_0043278 were transfected into MDA-MB-231 and MCF-7 cells, respectively. The effects of hsa_circ_0043278 on tumour cell growth, migration and invasion were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), colony formation, wound healing and Transwell assays in vitro. A xenograft experiment was conducted to validate the inhibitory effect of hsa_circ_0043278 on tumour growth. The interaction between hsa_circ_0043278 and miR-455-3p was confirmed by a dual-luciferase reporter assay. Mimics and inhibitors of miR-455-3p were designed to confirm the influence of hsa_circ_0043278 on the hsa_circ_0043278/miR-455-3p/etoposide-induced gene 24 (EI24) axis.ResultsHsa_circ_0043278 was downregulated in BC cell lines. Furthermore, overexpression of hsa_circ_0043278 notably decreased BC cell viability and inhibited BC cell migration and invasion in vitro and suppressed tumour growth in vivo. Downregulation of hsa_circ_0043278 led to the opposite results. Hsa_circ_0043278 expression was negatively correlated with that of miR-455-3p. In addition, mechanistic investigation proved that hsa_circ_0043278 directly bound to miR-455-3p and regulated EI24 and NF-κB expression in BC cells.ConclusionHsa_circ_0043278 acts as a tumour suppressor gene in BC through the hsa_circ_0043278/miR-455-3p/EI24 axis and may be regarded as a new prognostic predictor or potential therapeutic target in BC.

Project description:BackgroundBreast cancer (BC) remains the most prevalent malignancy and the leading cause of cancer death. Circular RNAs (circRNAs) have been discovered to serve as crucial regulators in BC. In the current work, we aimed to study the impact of circRAD18 (hsa_circ_0002453) on BC progression and mechanism governing it.Materials and MethodsThe expression levels of circRAD18, miR-613 and hexokinase 2 (HK2) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). CircRAD18 identification was performed using RNase R digestion and actinomycin D assay. Cell viability, colony formation, apoptosis, migration, invasion and glycolysis were measured by Cell Counting Kit-8 assay, colony formation assay, flow cytometry, transwell analysis and extracellular acidification rate detection assay, respectively. Western blot was used to assess the levels of E-Cadherin, Vimentin, N-Cadherin and HK2 protein. The targeted interplay between miR-613 and circRAD18 or HK2 was detected by dual-luciferase reporter assay. Xenograft model assay was performed to observe the role of circRAD18 in vivo.ResultsCircRAD18 was highly expressed in BC tissues and cells. CircRAD18 depletion hindered BC cell malignant behaviors, as evidenced by the inhibition in cell viability, colony formation, migration, invasion, epithelial to mesenchymal transition and glycolysis, as well as the promotion in cell apoptosis. CircRAD18 directly interacted with miR-613, and miR-613 mediated the repressive effect of circRAD18 knockdown on BC cell malignant behaviors. Moreover, HK2 was a direct target of miR-613, and circRAD18 positively regulated HK2 expression via sponging miR-613. Additionally, circRAD18 knockdown repressed tumor growth in vivo by miR-613.ConclusionOur current work suggested that circRAD18 silencing suppressed BC cell malignant behaviors in vitro and tumor growth in vivo at least partly via the regulation of the miR-613/HK2 axis, highlighting that circRAD18 might be a promising therapeutic target for BC treatment.

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Knockdown of SETDB1 inhibits breast cancer progression by miR-381-3p-related regulation.

Publications

Knockdown of SETDB1 inhibits breast cancer progression by miR-381-3p-related regulation.

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