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

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.