MicroRNAs (miRNAs) have been demonstrated to suppress the expression of critical cancer-related genes and are implicated in the development and progression of human cancer (Calin and Croce, 2006). MicroRNAs exert inhibitory activity by interacting with ZEB1 mRNA on its 3′untranslated regions (UTRs), repressing ZEB1 expression post-transcriptionally or inducing mRNA degradation (Esquela-Kerscher and Slack, 2006). Y-box binding protein 1 (YB1) inhibits the maturation of miR-205 and miR-200b through binding to microprocessors or uridylyl transferases. The downregulation of miR-205 and miR-200b enhances ZEB1 transcription, resulting in enhanced cell movement and malignant transformation (Liu et al., 2021). Other studies have shown that miR-369 inhibits the expression of ZEB1 mRNA and protein by interacting with its 3′-UTR in HCC cells. MiR-369 highly expresses in HCC and inhibits EMT by promoting the expression of E-cadherin while decreasing the expression of the mesenchymal biomarkers vimentin and N-cadherin (Dong Y. et al., 2021). Li and colleagues reported that miR-708 could decrease the expression of ZEB1 by specifically interacting with ZEB1 mRNA on its 3′-UTR, and therefore inhibit the growth, proliferation, and metastasis of HCC through mediating Wnt/β-Catenin signal (Li LY. et al., 2021).

ZEB1 is used as the substrate of E3 ubiquitin ligase. Tumor suppressor genes DDB1 and CUL4 are the core components of CRL4-DCAF15 (DDB1 and CUL4 associated factor 15), E3 ubiquitin ligase, which specifically recognizes zinc finger domain on the N-terminal of ZEB1 and promotes ZEB1 ubiquitination and degradation, thereby suppressing cell growth, proliferation, and metastasis as well as EMT in HCC cells (Dong X. et al., 2021). Other studies have shown that Ubiquitin-specific peptidase 39 (USP39) deubiquitinates and suppresses ZEB1 degradation, thus promoting the development of EMT and the onset of hepatocellular carcinoma. E3 ligase TRIM26 also degrades ZEB1 through ubiquitination and inhibits cell growth, development, and metastasis of HCC. USP39 and TRIM26 bind to each other directly and maintain the ubiquitin level of ZEB1, thus determining the proliferation and migration of HCC (Li X. et al., 2021).

Zinc finger protein acts on the key enzyme regulating the rate-limiting stage in glycolysis, and promotes or inhibits the aerobic glycolysis of tumor cells by up-regulating or inhibiting the rate-limiting enzyme. For example, there are two isoforms of pyruvate kinase M(PKM). PKM1 is abundant in mature cells, which increases ATP production, while PKM2 is commonly abundant in embryos and cancer tissue, which boosts the Warburg’s effect of HCC (Yang and Lu, 2013). The expression of PKM2 offers cancer a selective survival benefit. PKM2 participates in the metabolism of cancer reprogramming, and promotes tumor growth and development, which prompt people to study the metabolic and regulatory process behind the role of PKM2 in HCC (Benjamin Daniel et al., 2012).

Past research has discovered that E3 ligase ZFP91 interacts with hnRNP A1, a splicing regulator, to boost proteasome degradation of hnRNP A1. As a result, hnRNP A1-dependent PKM mRNA pre-mRNA splicing is inhibited, causing PKM1 isoform formation while inhibiting PKM2 isoform formation. The results show that ZEP91 inhibits liver cancer cells growth and proliferation, which participates in ubiquitination and catabolism of substrates, and suppresses metabolic programming, cell growth, and development of liver cancer (Chen et al., 2020).

The latest study found that silencing ZEB1 in different HCC cell lines substantially reduced levels of protein and aerobic glycolysis of the muscle isoform of phosphofructokinase-1 (PFKM), another rate-limiting enzyme in glycolysis, which was characterized by a decrease in glucose uptake and lactic acid production. The exogenous expression of PFKM significantly reduced this decline. Further study found that ZEB1 interacts with the non-classical ZEB1 binding motif in the PFKM promoter region, thus activating its transcription (Zhou et al., 2021). It is suggested that a new mechanism of direct relationship between zinc finger protein and promoting glycolysis and Warburg effect in the development of HCC.

Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism, which encourages the development and proliferation of liver cancer through the uptake of exogenous lipids. It has been found that LPL is the target of ZHX2. In NAFLD, ZHX2 inhibits NAFLD-HCC progression and cell growth retardation through transcriptional inhibition of LPL expression. In HCC cells, ZHX2 inhibits LPL and further suppresses the proliferation, lipid deposition, growth, and formation of exogenic and spontaneous tumors (Wu et al., 2020). Further studies found that ZHX2 boosted the transcription of miR-24–3p, which aimed at SREBP1c and caused its destruction. Moreover, ZHX2 inhibited de novo lipogenesis (DNL) and the development and transfer of HCC (Wu et al., 2020).

Sterol-responsive element-binding protein 1c (SREBP1c) is an important TF for DHL and is an important link between tumor signal transduction and tumor metabolism (Lee et al., 2019). SREBP1c participates in the production of cholesterol and fatty acids and has been proven to be overexpressed in HCC (Guo et al., 2014). Tumor cells reactivate DNL to provide nutrition for tumor cells, which is conducive to tumor cell growth and tumor symbiosis (Schulze and Harris, 2012). Therefore, zinc finger protein can delay the progression from NAFLD to HCC and the growth and invasion of HCC via transcriptional control of key regulatory factors in DNL.

ZNF451 is a class of SUMO E3 ligases and a multifunctional DDR factor, containing two N-terminal SIM domains and a ubiquitin-interacting motif. Extensive biochemical analysis shows that the C2H2-ZF domains and tandem SIM domains are the keys to its E3 ligase activity (Cappadocia et al., 2015; Eisenhardt et al., 2015; Schellenberg et al., 2017). ZNF451 and Topoisomerase 2 (TOP2) are involved in DDR and break the DNA double helix and topological changes (Deweese and Osheroff, 2009; Schellenberg et al., 2017), which could affect DNA supercoil formation during transcription and replication, and lead to genomic instability (Ju et al., 2006; Pommier, 2013; Tammaro et al., 2013; Madabhushi et al., 2015). Shanbhag found that DNA double-strand breaks (DSB) cause extensive local and global changes in chromatin structure, many of which depend on ATM kinases, leading to transcriptional silencing (Shanbhag et al., 2010). DNA double-strand break (DSB), one of the main types of DNA damage, promotes cell cycle halt and DDR to maintain the integrity of the genome via activating a series of cell activities.

CDC6 can protect the integrity of the genome via activating DDR (Yoshida et al., 2010), but overexpression of CDC6 may lead to repetitive replication and genomic instability, which is essential for tumor progression (Liontos et al., 2007). Zhang and colleagues proposed a new pathway of ZNF143-MDIG-CDC6 regulating in liver cells (Zhang et al., 2020). In addition, Understanding the interplay between transcription and DNA repair mechanisms will give critical insights and, eventually, novel therapeutic options for a variety of disorders linked with genome maintenance abnormalities (Sebastian and Oberdoerffer, 2017).

C2H2-ZF protein has become a key controller of telomere length. Dan has shown that zinc finger and SCAN domain containing 4 (Zscan4) inhibits telomere extension linked with the expression of Zscan4 by recruiting Uhrf1 and Dnmt1 (the main component of DNA methylation mechanism) and promoting their degradation, blocking DNA demethylation (Dan et al., 2017).

ZNF827 is abundant in telomeres and uses the ALT pathway to recruit DNA repair factors, which encourage homologous recombination and telomere lengthening. Conomos believe that ZNF827 attachment to human telomeres induces telomeric chromatin modification and the formation of an atmosphere that encourages telomere-telomere recombination, as well as the integration and regulation of numerous molecular components of ALT function (Conomos et al., 2014).

ZBTB48 (also known as HKR3 or TZAP) has 11 C2H2-ZF domains, three of which interact with TTAGGG motifs specifically. It was found that ZBTB48 binds to double-stranded TTAGGG repeats and acts as a negative regulator on telomeres (Li J. et al., 2017; Jahn et al., 2017; Kappei et al., 2017). When ZBTB48 is located at telomeres, a process called telomere trimming is triggered, resulting in the rapid deletion of telomere repeat sequences (Li J. et al., 2017). Due to the phenomenon that telomere maintenance is commonly and initially changed in HCC, telomerase targeting is a promising anti-cancer strategy.

ZEB1-induced EMT can lead to resistance to conventional chemotherapy. ZEB1 can classify hepatocellular carcinoma into epithelial type and mesenchymal type in vivo and in vitro. Mesenchymal/metastatic cancer cells need to activate the protein kinase C (PKC) pathway to survive (Singh et al., 2009). Sreekumar and colleagues have demonstrated that the PKC signal is stimulated in mesenchymal HCC cells, which helps them proliferate. Mesenchymal cells and chemotherapy-resistant cells that express ZEB1 are dependent on PKCa, which can be eliminated selectively by PKC inhibitor UCN-01. The inactivation of PKCa also reduces the activity of HCC, showing that UCN-01 in conjunction with chemotherapy can improve the therapeutic effect of ZEB1-positive HCC (Sreekumar et al., 2019). LONG studies have shown that the upregulation of ZEB1 expression is associated with the EMT characteristics of HCC, while inhibition of ZEB1 expression makes cells sensitive to chemotherapy (Long et al., 2019). Targeted inhibition of the ZEB1 gene may contribute to clinical chemotherapy resistance.

ZEB2 has a significant impact on the progression of HCC by regulating EMT. The interaction between Linc-ROR and miR-145 upregulates the transcription of ZEB2, which promote the proliferation and metastasis of HCC cells (Li C. et al., 2017). Recent research found that miR-212–3p reduces the transcription of ZEB2 and reduces the EMT, migration, and metastasis of HCC by targeting ZEB2, thus reducing paclitaxel resistance, which provides a new target for liver cancer chemotherapy (Yang et al., 2020).

Snail family transcriptional repressor 2 (SNAI2/Slug), belongs to the part of the Snail family of C2H2-ZF TFs and is a transcriptional repressor that interacts with E-box domains (Hajra et al., 2002). Slug is the key regulator of EMT, inducing EMT and inhibiting E-cadherin in various epithelial cells (Shih et al., 2005; Uchikado et al., 2005). Previous studies have shown that Slug inhibits multidrug resistance by inhibiting ABCB1 in vivo and in vitro, thus exerting tumor inhibitory effect (Hoshida et al., 2016). In contrast, recent research has shown that ABCB1 is downregulated in HCC cells undergoing EMT, while chemotherapy resistance to cisplatin has more than doubled. It is concluded that the chemotherapy resistance of HCC is sometimes influenced by changing Slug. The expression of Slug could affect chemotherapy resistance, depending on the cell environment (Karaosmanoglu et al., 2018).

Hedgehog (HH) signaling pathway is closely related to cancer growth and differentiation. Abnormal HH signal has been considered to be an important signal pathway and therapeutic target for human tumors (Lum and Beachy, 2004). HH signal is closely related to many basic processes, and the imbalance of this signal axis may lead to tumor occurrence, metastasis, and drug resistance. HH signaling has been found to promote tumor development at the molecular level by influencing tumor growth, EMT, CSC development, and acquired drug resistance (Ochoa et al., 2010; Sari et al., 2018). C2H2-ZF protein GLI1, the terminal effector of HH signaling, is a potential marker of signaling activation because it promotes gene expression. Chen and colleagues have found that EMT and elevated HH signaling activation may be causes of chemical resistance and invasion in poorly differentiated HCC cells (Chen et al., 2011). Further study showed that the protein level of GLI1 in poorly differentiated HCC cells was significantly increased. After the decrease of GLI1 expression, the responsiveness of HCC cells to doxorubicin and cisplatin increased significantly. Targeted HH signaling pathway gives a fresh viewpoint on drug resistance in the treatment of HCC (Zhou et al., 2020).

ZNF687 upregulates pluripotency-related factors. Overexpression of ZNF687 made cisplatin-treated liver cells resistant to apoptosis, and silencing ZNF687 significantly enhanced the sensitivity of HCC to cisplatin. These results indicate that ZNF687 has a significant impact on the chemical resistance of HCC (Zhang et al., 2017).

Zinc finger protein X-linked (ZFX) binds to the promoters of Nanog and SOX2 to promote tumor growth. In contrast, the knockout of ZFX increases the chemotherapeutic responsiveness to HCC (Wang et al., 2017). ZHX2 inhibited the demethylation of SOX2, Nanog, and Oct4, and inhibited the chemical resistance of liver cancer (Lin et al., 2020).