**1. Introduction**

Cancer is the leading cause of death all over the world, accounting for nearly 10 million deaths in 2020 according to the World Health Organization (WHO). Metastatic cancer, the main contributor to high mortality, results in more than 90% of cancer death. This is because when cancer metastasizes to distant organs, especially the bone, liver, lung, and brain, this secondary tumor is formed. And this kind of tumor is difficult to remove despite the various systemic treatments including chemotherapy, screening, and immunotherapy. Efforts from doctors, researchers, and other aspects to promote cancer killing over the past years have paid off in some countries and in some cancers. Since 1991, the cancer death rate has fallen continuously in the United States. Up to 2018, the total mortality rate fell by 31%. Yet the mortality rate has been increasing in other places, such as China [1]. In most cases, many patients with metastatic cancer will face death within 5 years after their diagnosis, which is a horrible thing. Therefore, knowing the mechanism of cancer metastasis to treat metastasis is meaningful for patients, and is a challenging project for oncologists and clinical investigators.

Exploring the physiological mechanisms of the metastatic process is the foundation to find successful interventions. In the beginning, body fluids were thought to be responsible for tumor metastasis. In 1929, James Ewing proposed a theory that

believed the anatomical structure of the vascular system contributes to metastasis and dissemination of cancer cells [2]. This view prevailed for decades. Nonetheless, the most classic and now popular is the "seed and soil" hypothesis proposed by Stephen Paget in 1889 [3]. Over the next few decades, cancer scientists gradually enhanced our knowledge of this mechanism based on molecular and cellular aspects. During this process of metastasis, countless molecules, and complex pathways, including epigenetic regulations, are involved in the dissemination and colonization of cancer cells from a primary tumor at metastatic sites. Epigenetics, a reversible process, refers to the study of heritable changes in gene expression without DNA sequence changes. Increasing studies of epigenetic regulation suggest that such regulations without altering the DNA sequence are critical for the normal physiological activities and the maintenance and development of tissue-specific gene expression in mammals [4]. The location of modified residue and the degree of methylation determines whether the transcriptional activation or repression. For example, the trimethylation of lysine 4 on histone H3 (H3K4me3) can be observed at the promoters of activated genes transcriptionally, yet trimethylation of H3K9 (H3K9me3) and H3K27 (H3K27me3) is enriched at repressed gene promoters transcriptionally [5].

Moreover, the importance of epigenetic changes in early tumorigenesis and cancer metastasis also has been shown, including non-coding RNA (ncRNA), DNA methylation, and histone modifications. Some such examples are increased N6-methyladenosine (m6A) modification of c-Myc mRNA enhances tumor cell growth, invasion, and tumorigenesis in animal models [6]. Upregulated Lysine Demethylase 6B (KDM6B) facilitates lung metastasis in osteosarcoma by modulating the H3K27me3 demethylation level of lactate dehydrogenase (LDHA) [7]. In addition, the enhancer of zeste homolog 2 (EZH2), the histone methyltransferase (HMT) of H3K27, is increased in cancers and promotes tumor metastasis [8, 9]. overexpressed long non-coding RNA (lncRNA) H19 enhances the migration of malignant cells and promotes the occurrence of epithelial to mesenchymal transition (EMT) in endometrial cancer [10].

Given the distinguished functions of epigenetics in cancer progression, and numerous crucial pathways and key biomarkers discovered by researchers, various potent and specific inhibitors targeting biomarkers have been studied and applied in clinics for treating cancer, since azacytidine, the first epigenetic drug approved by Food and Drug Administration (FDA) in 2004. In addition, as inhibitors of DNA methyltransferase (DNMT) enzymes (also termed hypomethylating agents), decitabine (5-aza-2′-deoxycytidine) and guadecitabin are the most extensively applied epigenetic therapies to kill various cancer cells, such as mutated monocyte in acute myeloid leukemia (AML) [11]. Several histone deacetylase (HDAC) inhibitors also have been extensively applied to anticancer (*i.e.,* vorinostat, romidepsin, panobinostat, and belinostat), gaining the approval of FAD for hematological malignancies based on the activity of the single drug [12]. What's more, histone methyltransferase (HMTs), like EZH2, protein arginine methyltransferase 6 (PRMT6), SET domain bifurcated 1 (SETDB1), SUV39H1, and disruptor of telomeric silencing 1-like (DOT1L), also are the targets of cancer treatment. Note that, several smallmolecule inhibitors of EZH2 (*i.e.,*tazemetostat, SHR2554, MAK683) and DOT1L (i.e., EPZ-5676) have entered into clinic phases [13].

Based on the increasing knowledge about the mechanism of metastasis and drug development, the prognosis and survival in patients with cancer will gain an effective improvement in clinical outcomes. That is because using the vulnerabilities of
