**7. Epigenetic modification and EMT**

EMT is a comprehensive reprogramming during tumor development. This process involves metabolism, epigenetics, and differentiation. In a specific tumor microenvironment, EMTdedifferentiated cells escape the primary tumor after they acquire migration and invasion capabilities, invade the surrounding tissues, enter into the blood or lymphatic vessels, and settle in distant organs. EMT converts differentiated epithelial cancer cells to an undifferenti‐ ated state, thereby expressing stem cell markers and acquiring stem cell-like functions. This process is reversible, and mesenchymal cells can differentiate into epithelial phenotypes. Thus, an important process is developed in the macroscopic metastases in different organs.

DNA methylation, histone modification, and microRNA are the three types of epigenetic modification. Many studies have shown that epigenetic modifications play a key role in tumor metastasis [81]. The downregulation of E-cadherin (a cell adhesion molecule) expression during EMT is an important feature. Therefore, the precise regulation of E-cadherin expression via epigenetic modifications is extremely important to the occurrence of EMT. Several EMTrelated transcription factors are recruited as E-cadherin gene promoter, which inhibits transcription [4]. Studies have shown that E-cadherin can be inhibited by the synergy of various histone modification enzymes. The E-cadherin gene promoter is inhibited to different extents to silence E-cadherin expression [82].

The characteristics of EMT are reversible in the type of stem cells and malignant features. Tumor stem cells are unique undifferentiated cells, rather than increasing diffusion, compared with most differentiated epithelial cells. The diffusion of anabolic needs is related to the maintenance of an undifferentiated state, which may be metabolic alterations of the links between EMT and tumor [83]. A change in cell metabolism is an important sign of cancer. The best metabolic phenotype in tumor cell is characterized by the Warburg effect, which proves that ATP is not the only metabolite of tumor cells [84]. Further studies have shown that aerobic glycolysis can better satisfy the basic needs of cell division, known as the post-Warburg model. This process is not only associated with cancer and normal cell proliferation, but also inhibits mitotic cell differentiation. In the same inducers, bunah and inactivated tumor suppressor genes, even oxygen glycolysis capability increased in the EMT, can be attributed to cell undifferentiated state. The appropriate energy level is sufficient for biosynthesis precursor, balancing normal state, and maintaining an undifferentiated state.

Epigenetic modifications are complex, dynamic, and connected with the extracellular envi‐ ronment and nuclear transcription. Energy availability is extremely important. Energy-rich substances, such as carbohydrates and fats, in the human body translate into ATP, along with a large number of metabolites, such as glycolysis and fatty acid oxidation. These metabolites can also drive epigenetic modifications in gene expression. A change in the intermediate metabolites of EMT may not be simple. Metabolic reprogramming plays a role in the energy crisis causation of cancer cells. This process determines the epigenetic sand by modifying the undifferentiated state of the chromatin structure. Reprogrammed genes and the change in gene expression influence EMT markers and metabolic enzymes to overcome the local restriction to obtain energy in the distant tissues and organs. The microenvironment is significant for the EMT metastasis potential of cancer cells in reprogramming metabolism, epigenetics, and differentiation. Hepatic, epidermal, and fibroblast growth factors activate and maintain the EMT process. The cancer microenvironment growth factor activity generally regulates the interaction between metabolism and EMT to coordinate cell differentiation and metabolism.

The transfer process is the key to the reversibility of EMT based on our previous study, in which EMT regulation is mainly at the transcription level [4]. However, numerous molecular mechanisms cooperate to change the behavior of tumor cells. In particular, the role of the transcription regulation of EMT in the regulation and control of gene expression of the transcription of alternative splicing is extremely important. Spliceosome assembly has experienced gradual, composition, and structure changes required for normal maintenance. The correlation of alternative splicing tumor progression becomes apparent. In fact, all major cell biology deregulations of cancer are related to the changes in the alternative splicing of a specific gene profile. Modifying the splicing expression and activities supervised by SR and hnRNP provides the main source of changes in the stitching program observed in cancer cells [85].

Malignant EMT plays a key role during transfer, and the alternative splicing program affects the cell phenotype, including protein, cell adhesion, and cytoskeleton dynamics, influences tumor microenvironment, and controls tumor metastasis formation. Cancer gene mutations initiate processes, and epigenetic changes will be necessary to promote cancer. The change in the epigenome improves the transfer of cells.

In general, cells, which are affected by external environment signals, satisfy the internal requirements of nutrient and energy metabolism, as well as cooperate actively to promote the occurrence of EMT. Thus, tumor metabolic adaptations and EMT are different mechanisms for the same target cells to survive and grow. A close link and high correlation exist between metabolic reprogramming EMT and the similarity rule and fly mechanism.
