A feedback loop between lncRNA MALAT1 and DNMT1 promotes triple-negative breast cancer stemness and tumorigenesis

Yu Hu; Yuqiong He; Na Luo; Xin Li; Lei Guo; Kejing Zhang

doi:10.1080/15384047.2023.2235768

A feedback loop between lncRNA MALAT1 and DNMT1 promotes triple-negative breast cancer stemness and tumorigenesis

Cancer Biol Ther. 2023 Dec 31;24(1):2235768. doi: 10.1080/15384047.2023.2235768.

Authors

Yu Hu^{1

2}, Yuqiong He^{1

2}, Na Luo^{1

2}, Xin Li^{1

2}, Lei Guo^{1

2}, Kejing Zhang^{1

2}

Affiliations

¹ Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China.
² Department of General Surgery, Xiangya Hospital, Central South University, Clinical Research Center for Breast Cancer in Hunan Province, Changsha, Hunan Province, P.R. China.

Abstract

Background: The function of long non-coding RNA (lncRNA) MALAT1 in regulating triple-negative breast cancer (TNBC) stemness and tumorigenesis was investigated.

Methods: Sphere formation and colony formation assays coupled with flow cytometry were employed to evaluate the percentage of CD44^high/CD44^low cells, and ALDH⁺ cells were performed to evaluate the stemness. Bisulfite sequencing PCR (BSP) was employed to detect the methylation level of MALAT1. Tumor xenograft experiment was performed to evaluate tumorigenesis in vivo. Finally, dual-luciferase reporter and RIP assays were employed to verify the binding relationship between MALAT1 and miR-137.

Results: Our results revealed that MALAT1 and BCL11A were highly expressed in TNBC, while miR-137 and DNMT1 were lowly expressed. Our results proved that MALAT1 positively regulated BCL11A expression through targeting miR-137. Functional experiments revealed that MALAT1 inhibited DNMT1 expression through acting on the miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis. We also found that high MALAT1 expression in TNBC was related to the DNMT1-mediated hypomethylation of MALAT1. As expected, DNMT1 overexpression could remarkably inhibit TNBC stemness and tumorigenesis, which was eliminated by MALAT1 overexpression.

Conclusion: MALAT1 downregulated DNMT1 by miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis; meanwhile, DNMT1/MALAT1 formed a positive feedback loop to continuously promote TNBC malignant behaviors.

Keywords: BCL11A; DNMT1; MALAT1; MiR-137; cell stemness; positive feedback loop; triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis / genetics
Cell Line, Tumor
Cell Proliferation / genetics
Cell Transformation, Neoplastic / genetics
DNA (Cytosine-5-)-Methyltransferase 1* / genetics
DNA (Cytosine-5-)-Methyltransferase 1* / metabolism
Feedback
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs* / genetics
MicroRNAs* / metabolism
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Triple Negative Breast Neoplasms* / pathology

Substances

MicroRNAs
MIRN137 microRNA, human
RNA, Long Noncoding
DNMT1 protein, human
DNA (Cytosine-5-)-Methyltransferase 1
MALAT1 long non-coding RNA, human

Grants and funding

This work was supported by the Natural Science Foundation of Hunan Province-Youth Fund Project: The Role of MALAT1/mir-137/BCL11A/DNMT1 Circuit on Triple Negative Breast Cancer Stem Cells (No. S2020JJQNJJ0014) and Beijing Medical Health Foundation (No.YWJKJJHKYJJ-B17465).