Journal of Cell Signaling
Open Access

PRMT1-SMAD7 Signaling Bridges Stemness and Epithelial-Mesenchymal Transition

Derynck Sucov^{* *}Correspondence: Derynck Sucov, Department of Tissue Biology and Stem Cell Research, University of California, San Francisco, California, USA, Email:

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Description

PRMT1 is essential for TGF-induced expression of core EMT-TF, including ZEB1 and ZEB2, Snail, and Slug, as a result of the regulation of TGF/SMAD signalling. Numerous studies have been conducted on the effects of Epithelial-Mesenchymal Transition (EMT) on cell shape and motility, particularly in the invasion and metastasis of cancer. In more recent times, it has become clearer how EMT and Cancer Stem Cells (CSCs) are related. According to one definition of the CSC, it is a group of cells with characteristics similar to those of stem cells and the capacity to start a tumor's growth and produce a tumor mass. Many cancer types, including breast, lung, pancreatic, and colon carcinomas, have been shown to increase the acquisition of stem-like features when EMT, or a partial EMT, is present. By suppressing the production of miRNAs that impede stemness, EMT-TF ZEB1 was originally discovered to be necessary for stemness in pancreatic cancer. Slug and Snail, two EMT-TFs, have been demonstrated to support the stemness of mammary epithelial cells and breast tumor-initiating cells in the mammary gland in conjunction with ZEB1.

In breast cancer and skin squamous cell carcinomas, TGF, a pluripotent cytokine, contributes to the development of cancer stem cells and, thus, the genesis of tumors. We found that TGF-induced stem cell formation required PRMT1-mediated SMAD7 methylation, which enhanced EMT-TF expression. In human mammary epithelial cells, the inhibition of PRMT1 greatly inhibited the expansion of the CD44highCD24low cell population, which is a marker for epithelial stem cells. It was investigated how the protein markers for mammary epithelial stem cells, such as CD44, KLF4, BMI1, POU5F1, and NANOG, were indicated. The outcome demonstrated that TGF-induced stimulation of the expression of those stemness genes and mammosphere development was severely reduced by PRMT1 silencing. Our findings showed that TGF/SMAD signalling was made possible by PRMT1's methylation of SMAD7, which promoted the expression of EMT-TF, the advancement of EMT, and the development of cancer stem cells. These observations also offer more proof between stemness and EMT.

Reduced expression of SMAD7, a crucial intrinsic negative regulator of the TGF/SMAD signalling pathway, increases TGF-induced EMT and tumor metastasis. In Hepatocellular Carcinoma (HCC), breast cancer, melanoma, glioblastoma, and renal cancer, lower SMAD7 expression has been linked to shorter recurrence-free survival and inferior overall survival. AML and melanoma are two cancer forms where elevated SMAD7 expression has been linked to a worse prognosis. However, some investigations have shown the reverse findings. SMAD7 was found to play a dual role in Colorectal Cancer (CRC), as it might be linked to either a better or worse prognosis. The bidirectional regulation of cancer by TGF may explain the correlation between SMAD7 expression and cancer prognosis.

Despite the contentious significance of SMAD7 in cancer prognosis, it is significant that SMAD7's function in maintaining CSCs' stemness is beginning to be understood. According to studies, SMAD7 expression suppression increases the stemness of CSCs in HCC, breast cancer, Nasopharyngeal Carcinoma (NPC), and glioma. More significantly, it was discovered that SMAD7 ubiquitination, one of the best known PTMs of SMAD7, promotes CSC stemness by encouraging its degradation. We showed that SMAD7 stability was lowered and epithelial stemness was controlled by PRMT1-catalyzed methylation. Together, these results show that SMAD7 plays a role in preserving the stemness of CSCs.

Conclusion

It has been discovered that PRMT1 exhibits abnormal expression in a number of cancer types, including breast, prostate, colon, and leukaemia. It has been shown to play a part in telomere maintenance, DNA repair, apoptosis, and the response to oxidative stress in the development of cancer. According to most reports, higher PRMT1 expression is linked to a poor prognosis. According to our findings, PRMT1 promotes EMT throughout the development of tumors in a variety of cancer types. Recently, we discovered that PRMT1 regulates epicardial differentiation and EMT during heart development by interfering with p53 stability, further demonstrating the crucial functions of PRMT1 in EMT and stemness. CSC stemness, which is essential for carcinogenesis, therapy resistance, and consequently tumor relapse after treatment, has the potential to be promoted by EMT. We have shown that TGF/SMAD signalling and TGF-induced EMT depend on PRMT1-induced SMAD7 methylation, which sheds light on the functions of PRMT1 and the associated SMAD7 methylation in CSCs-related carcinogenesis, therapy resistance, and therefore tumor relapse after treatment. Our findings suggest that PRMT1 and SMAD7 methylation are possible therapeutic targets for the spread and recurrence of tumors.