An epigenetic perspective on tumorigenesis: Loss of cell identity, enhancer switching, and NamiRNA network.

Various tumorigenic theories have been proposed in the past century, which contribute to the prevention and treatment of cancer clinically. However, the underlying mechanisms of the initiation of cancer, drug resistance, neoplasm relapse, and metastasis are still challenging to be panoramically addressed. Based on the abundant evidence provided by others and us, we postulate that Tumor Initiated by Loss of Cell Identity (LOCI), which is an inevitable initiating event of tumorigenesis. As a result, normal cells are transformed into the cancerous cell. In this process, epigenetic regulatory program, especially NamiRNA (Nuclear activating miRNA)-enhancer-gene activation network, is vital for the cell identity. The disorganization of NamiRNA-enhancer-gene activation network is a causal predisposition to the cell identity loss, and the altered cell identity is stabilized by genetic variations of the NamiRNA-enhancer-gene activation network. Furthermore, the additional genetic or epigenetic abnormities confer those cells to carcinogenic characteristics, such as growth advantage over normal cells, and finally yield cancer. In this review, we literally explain our tumor initiation hypothesis based on the corresponding evidence, which will not only help to refresh our understanding of tumorigenesis but also bring benefits to developing "cell identity reversing" based therapies.