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YY1-mediated long non-coding RNA Kcnq1ot1 promotes the tumor progression by regulating PTEN via DNMT1 in triple negative breast cancer

Cancer Gene Therapy volume 28, pages 1099–1112 (2021)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive cancer, and rapidly progresses following relapse in advanced stage. This cancer is usually associated with worse overall survival, so the carcinogenesis of TNBC needs to be further explored to find more effective therapies. In this study, we intended to identify the roles of YY1-mediated long non-coding RNA Kcnq1ot1 in TNBC. First, the paired samples of tumor tissues and adjacent tissues were collected to determine YY1, lncRNA Kcnq1ot1, and PTEN expression using RT-qPCR and Western blot analysis followed by analysis of the relationship between them and patient survival. The results revealed that YY1 and lncRNA Kcnq1ot1 were upregulated in TNBC tissues, and high expression of YY1 and lncRNA Kcnq1ot1 was associated with poor patient survival. Then, ChIP and MSP assays were employed to explore interactions between YY1, lncRNA Kcnq1ot1, and PTEN gene. We obtained that YY1 upregulated lncRNA Kcnq1ot1, which mediated PTEN methylation via DNMT1, thus decreasing PTEN expression. Afterward, TNBC cells were examined for their viability using functional assays with the results displaying that overexpression of YY1 facilitated TNBC cell proliferation, invasion, and migration. Mechanistically, upregulated YY1 repressed tumor growth by inhibiting PTEN via upregulation of lncRNA Kcnq1ot1. Mouse models were also constructed, and the above effects of YY1, lncRNA Kcnq1ot1, and PTEN on TNBC were also established in vivo. Taken together, this study demonstrates that the silencing of YY1 exerted tumor-suppressive effects on TNBC by modulating lncRNA Kcnq1ot1/DNMT1/PTEN pathway, in support of further investigation into anti-tumor therapy for TNBC.

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Fig. 1: YY1 was upregulated in TNBC tissues and cells and silencing of YY1 retarded TNBC cell viability, migration, and invasion.
Fig. 2: Overexpression of YY1 promoted proliferation, migration, and invasiveness of MCF-10A cells.
Fig. 3: YY1 facilitated TNBC progression by upregulating lncRNA Kcnq1ot1 expression.
Fig. 4: LncRNA Kcnq1ot1 was upregulated in TNBC tissues and cells and silencing of lncRNA Kcnq1ot1 retarded TNBC cell viability, migration, and invasion.
Fig. 5: LncRNA Kcnq1ot1 inhibited TNBC cell viability, migration, and invasion by suppressing PTEN expression.
Fig. 6: LncRNA Kcnq1ot1 RNA mediated PTEN methylation through its interactions with Dnmt1.
Fig. 7: YY1 inhibited PTEN expression through lncRNA Kcnq1ot1-DNMT1 axis to promote the progression of TNBC.

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Funding

This work was supported by the Natural Science Foundation of Heilongjiang Province (No. H2018023), Science Research Fund for Youth Innovation of the Second Affiliated Hospital of Harbin Medical University (No. KYCX2019-05), Scientific Research Project of Health and Family Planning Commission in Heilongjiang Province (No. 2018250) and Postdoctoral Research Support Project of Heilongjiang Province (No. LBH-Z18269).

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  1. Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, PR China

    Bin Shen, Yang Li, Qian Ye & Youyou Qin

  2. Heilongjiang Academy of Medical Sciences, Harbin, 150086, PR China

    Youyou Qin

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Correspondence to Youyou Qin.

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Shen, B., Li, Y., Ye, Q. et al. YY1-mediated long non-coding RNA Kcnq1ot1 promotes the tumor progression by regulating PTEN via DNMT1 in triple negative breast cancer. Cancer Gene Ther 28, 1099–1112 (2021). https://doi.org/10.1038/s41417-020-00254-9

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