The Dual Function Of PRMT1 In Modulating Epithelial-mesenchymal Transition And Cellular Senescence In Breast Cancer Cells

In recent years, breast cancer has become the most frequently diagnosed cancer and one of the leading causes of cancer-related death in Chinese women. Most of breast cancer cases initiate from the mammary epithelial cells, and more than 90% of the fatality is attributable to the tumour metastasis. The metastatic process of tumour is facilitated through a number of steps; after a tumour mass has expanded at the primary site, some cells can acquire increased motility and be detached from the primary tumour. This step is achieved by breaking the natural barriers, such as the extracellular matrix to gain the access to the blood system.Typically, these cancer cells are characterized by their ability to migrate and colonize at remote sites, such as bone, lungs, brain and liver, where they proliferate to form new tumours.In epithelial cancers like breast cancer, metastasis is thought to occur via an epithelial-to-mesenchymal transition(EMT) programme.The EMT is a cellular process in which the epithelial cells lose their epithelial characteristics and acquire more mesenchymal properties through cytoskeleton rearrangements and alterations in adhesion, cellular structure and morphology. It has been well established that EMT not only facilitates the metastatic dissemination of tumours, but also is associated with stem cell traits, cancer therapy resistance, inhibition of senescence and suppression the host immune surveillance system. A number of growth factor signaling pathways, transcription factors, microRNAs, alternative splicing and epigenetic regulation mechanisms are have found to be involved in the regulation of EMT.Cellular senescence has been proposed as a crucial tumour-suppressive mechanism that causes irreversible cell cycle arrest against the initiation and progression of cancer. Findings from the senescence research field suggest the possibility that pro-senescence therapy involving the induction of a fixed cytostatic condition could be an effective way to treat cancer with less side effects. Interestingly, EMT and senescence, the two seemingly contrary biological processes, appear to be interlinked, with several common factors playing dominant roles in both settings. This may open new strategic therapeutic avenues by targeting the major players with a double impact in promoting EMT and senescence.The protein arginine methyltransferase 1(PRMT1), a predominant asymmetric arginine methyltransferase in human, has been shown to influence many cellular processes, including RNA processing, gene transcription, DNA damage repair, signal transduction and protein translocation. PRMT1 responses for a range of protein substrates, such as FOXO1, ERα,MRE11, 53BP1 and histone H4. Asymmetric dimethylation of histone H4 at arginine 3(H4R3me2as) mediated by PRMT1 is a critical modification for active chromatin. Increasing evidence has linked PRMT1 to the development and progression of cancers. Aberrant expression of PRMT1 has been observed in several cancers, including breast cancer, lung cancer, colon cancer, ladder cancer, acute myeloid leukemia and mixed lineage leukemia.However, the roles of PRMT1 in breast cancer progression and metastasis have not been elucidated. In this dissertation, we identified PRMT1 as a key regulator of EMT in breast cancer. We showed that the EMT program induced by PRMT1 endowed the human mammary epithelial cells with cancer stem cell properties. Moreover, PRMT1 promoted the migratory and invasive behaviors in breast cancer cells. We also demonstrated that abrogation of PRMT1 expression in breast cancer cells abated metastasis in vivo in a mouse model. In addition, knockdown of PRMT1 arrested cell growth in G1 tetraploidy and induced cellular senescence. Mechanistically, PRMT1 impacted EMT process and cellular senescence by mediating the asymmetric dimethylation of arginine 3 of histone H4(H4R3me2as) at the ZEB1 promoter to activate its transcription, indicating the essential roles of this epigenetic control both in EMT and in senescence.Thus, we unraveled a dual function of PRMT1 in modulation of both EMT and senescence via regulating ZEB1. This finding points to the potent value of PRMT1 as a dual therapeutic target for preventing metastasis and for inhibiting cancer cell growth in malignant breast cancer patients.