Our present study confirmed that the EZH2 gene had a higher expression level in tumors compared with controls and in advanced tumors compared with early-stage tumors. Hsa-let-7c-5p was upregulated in HCC tumors compared with controls and its expression was associated with a good prognosis in HCC patients. These results showed that the hsa-let-7c-5p-EZH2 axis might have a crucial role in the progression of HCC.
EZH2 is a core component of the PRC2 and trimethylates H3K27. Deregulation of EZH2 is associated with gene expression repression, tumorigenesis, development, and tumor cell radiosensitivity [5, 23–25]. EZH2 regulates downstream genes and signalings in a PRC2-independent manner [13]. EZH2 functions as both an oncogenic gene or as a tumor suppressor gene by activating its downstream target genes and signalings through a PRC2-independent way [13]. For instance, EZH2 directly binds to the promoter of the large tumor suppressor 2 (LATS2) gene and induces its H3K27me3 in gallbladder cancer cells [26]. EZH2 also decreases forkhead box C1 (FOXC1) expression by promoting H3K27me3 in breast cancers [27]. LATS2 is a member of the large tumor suppressor family [28, 29] and the FOXC1 transcription factor also as an oncogenic gene by regulating cell proliferation, senescence, angiogenesis, and metastasis [30, 31]. This evidence reveals the important role of EZH2 in human cancers.
Recent evidence shows that EZH2 regulates immune responses in human cancers, including HCC [4, 13, 32, 33]. Elevated EZH2 level was positively correlated with immunosuppression in HCC and was negatively correlated with the contents of Class I major histocompatibility complex molecules [4]. However, loss or knockdown of EZH2 in regulatory T cells and natural killer cells enhance their recruitment and anti-tumor immunity [34, 32]. Therefore, many efforts have been made to inhibit EZH2 methyltransferase activity, break PRC2’ structure, suppress EZH2 expression, or develop EZH2 inhibitors with low toxicity, high efficiency, and high selectivity in cancer treatment.
EZH2 and H3K27me3 levels could be regulated by non-coding RNAs [5, 35]. Many EZH2-related miRNAs, including tumor suppressor miRNAs hsa-let-7b, hsa-miR-101, and hsa-miR-26a have been identified [5, 36]. These miRNAs have tumor suppressive roles by inhibiting EZH2 and H3K27me3 levels and then abrogating the aggressive type of cancers [37, 5]. Xu et al [38] showed that hsa-miR-101 inhibited human HCC progression and promoted cytostatic drug sensitivity by suppressing EZH2. Also, miR-101-3p induces autophagy by targeting EZH2 [39]. We observed that EZH2 was negatively targeted by seven downregulated miRNAs in HCC, including hsa-let-7b-5p, hsa-let-7c-5p, hsa-miR-101-3p, hsa-miR-144-3p, hsa-miR-150-5p, hsa-miR-26a-5p, and hsa-miR-26b-5p. All miRNAs are associated with the proliferation and metastasis in HCC cells and prognosis in HCC patients [40–45]. Although the regulation of other miRNAs could regulate HCC cell proliferation, migration, and metastasis, only hsa-let-7c-5p was associated with prognosis in HCC patients in the TCGA database, showing that the role of the hsa-let-7c-5p-EZH2 axis in the HCC might be very important. Also, the involvement of EZH2 in microRNAs in cancer (hsa05206) showing miRNA-mediated EZH2 might play important roles in HCC development.
Song et al [46] confirmed the downregulation of hsa-let-7c-5p in HCC tumor tissues. They showed that a high level of hsa-let-7c-5p was correlated with a long overall survival period. Li et al. [47] confirmed that hsa-let-7c-5p and EZH2 were downregulated and upregulated in breast cancer tissues compared with controls, respectively. They also showed that the inhibition of hsa-let-7c-5p increased EZH2 expression in MDA-MB-231 breast cancer cells. However, there is poor information on the regulation of hsa-let-7c-5p on EZH2 and the axis in HCC. Therefore, identification of the hsa-let-7c-5p-EZH2 axis might provide a novel and reference to HCC mechanism. Also, the strategy focusing on inhibiting EZH2 might provide a reference for the treatment of HCC.