Epigenetically modulated miR-1224 suppresses the proliferation of HCC through CREB-mediated activation of YAP signaling pathway

Abstract

Mounting evidence has demonstrated that microRNA-1224 (miR-1224) is commonly downregulated and serves as a tumor suppressor in multiple malignancies. However, the role and mechanisms responsible for miR-1224 in hepatocellular carcinoma (HCC) remain unclear. In this study, we found that the expression of miR-1224 was downregulated in HCC. Low miR-1224 expression was associated with poor clinicopathologic features and short overall survival. Moreover, the methylation status of putative CpG islands was also found to be an important part in the modulation of miR-1224 expression. miR-1224 could induce HCC cells to arrest in G0/G1 phase and inhibited the proliferation of HCC cells both in vitro and in vivo. Mechanistic investigation showed that by binding with cyclic AMP (cAMP)-response element binding protein (CREB) miR-1224 could repress the transcription and the activation of Yesassociated protein (YAP) signaling pathway. Furthermore, the expression of miR-1224 was inhibited by CREB through EZH2-mediated histone 3 lysine 27 (H3K27me3) on miR-1224 promoter, thus forming a positive feedback circuit. Our findings identify a miR-1224/CREB feedback loop for HCC progression and that blocking this circuit may represent a promising target for HCC treatment.

The interplay between noncoding RNA and YAP/TAZ signaling in cancers: molecular functions and mechanisms

“…MiR-1224, functioning as a tumor suppressor, was found to be downregulated in hepatocellular carcinoma and to inhibit the proliferation of hepatocellular carcinoma cells both in vitro and in vivo. By binding to CREB, miR-1224 repressed its transcription and subsequent activation of the YAP signaling pathway in hepatocellular carcinoma cells [ 88 ].…”

The Role and Mechanism of microRNA-1224 in Human Cancer

“…In colorectal cancer (CRC), miR-1224-5p also acted as a tumor suppressor and a significant reduction of miR-1224-5p was detected in CRC tissues and cell lines according to qRT-PCR, western blot, and immunohistochemistry ( 17 , 38 , 39 ). In hepatocellular carcinoma (HCC) and pancreatic cancer (PC), miR-1224 showed a descending trend, especially the miR-1224-5p according to bioinformatics analysis (GEO datasets), RNA sequencing and qRT-PCR validation ( 42 – 46 ). Not only that, but miR-1224-5p also declined in esophageal squamous cell carcinoma (ESCC) and esophageal cancer (ESCA) tissues compared to normal tissues by qRT-PCR ( 40 , 41 ).…”

“…Yang et al. identified a miR-1224/CREB feedback loop, suggesting that blocking this circuit can be a potential molecular treatment for HCC patients ( 42 ). Similarly, miR-1224-3p/PGM5 axis played a vital role in cell proliferation, metastasis, and migration, and may be a potential target for therapy of BC ( 32 ).…”

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

“…However, the majority of studies point toward an oncogenic role of YAP and TAZ. Some of these have been listed in Table 2 ( Shen et al, 2018 ; Yang M. et al, 2019 ; Yang et al, 2021 ). Hippo kinases and their upstream regulators are not a part of the Wnt signaling but it is important to mention them since these regulate the nuclear levels of YAP/TAZ and as a result, β-catenin.…”