DNMT1 recruited by EZH2-mediated silencing of miR-484 contributes to the malignancy of cervical cancer cells through MMP14 and HNF1A

Abstract

BackgroundEmerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to cervical cancer (CC) tumorigenesis and development. Previous work showed that miR-484 which regulated the EMT process was obviously downregulated in CC. However, little is known about the precise mechanism.ResultsWe found that the deficiency of EZH2-recruited DNA methyltransferases DNMT1 reduced the CpG methylation of miR-484 promoter and then increased the miR-484 expression. Furthermore, the cell membrane-bound matrix metalloproteinase (MMP14) and the hepatocyte nuclear factor 1A (HNF1A) were found to be downregulated by miR-484. miR-484 repressed the expression of MMP14 and HNF1A inhibiting CC growth and metastasis in vitro and in vivo. Upregulation of MMP14 and HNF1A promotes the CC cell adhesion and EMT, all of which contribute to cell motility and metastasis. Moreover, miR-484 negatively regulates the WNT/MAPK and TNF signaling pathway by downregulating HNF1A and MMP14 respectively. Thus, miR-484, who is downregulated by DNMT1-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting MMP14 and HNF1A expression in CC.ConclusionOur finding characterizes miR-484 as a key suppressive regulator in CC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-484 silencing, expanding our understanding of the molecular mechanism underlying CC progression and metastasis.Graphical abstract

Tanshinone II A enhances pyroptosis and represses cell proliferation of HeLa cells by regulating miR-145/GSDMD signaling pathway

“…miRNA is a type of non-coding small RNA molecule, which has emerged as a critical molecular marker in development and progression of many cancers [43,44]. For instance, silencing of miR-484 could aggravate the malignancy of cervical cancer cells by inhibiting MMP14 and HNF1A [43].…”

“…miRNA is a type of non-coding small RNA molecule, which has emerged as a critical molecular marker in development and progression of many cancers [43,44]. For instance, silencing of miR-484 could aggravate the malignancy of cervical cancer cells by inhibiting MMP14 and HNF1A [43]. In addition, it was observed that exosomal miR-106b increased the MMP-2 and MMP-9 expression, leading to an enhancement of the migration and invasive ability of BEAS-2B cells [44].…”

<p>microRNA-26a Directly Targeting MMP14 and MMP16 Inhibits the Cancer Cell Proliferation, Migration and Invasion in Cutaneous Squamous Cell Carcinoma</p>

“…16 In addition, MMP14 and MMP16 also play important roles in the development of multiple tumors. [17][18][19][20] However, whether miR-26a regulates MMPs in CSCC remains elusive. The purpose of our study was to clarify the specific function of miR-26a in CSCC and to further clarify the regulation of miR-26a on MMPs.…”

LncRNA UCA1 promotes cisplatin resistance in gastric cancer via recruiting EZH2 and activating PI3K/AKT pathway

“…Furtherly, our results suggested that knockdown EZH2 could retort the UCA1-induced upregulation of p-PI3K and p-AKT. In addition, one-fifth of all human lncRNAs identified is physically associated with EZH2 [20,21]. To determine the association between UCA1 and EZH2, RIP and RNA pull down assay were performed.…”

“…EZH2 is a crucial component of PRC2, which was reported physically associated with one-fifth of lncRNAs to date [20,21]. We postulated that UCA1 may interact with and bind to EZH2 to regulate downstream molecular events in view of the regulation of UCA1 on EZH2 protein expression.…”