Solid Cancer Cells Can Differentiate Into Neuron-like Cells And Share A Regulatory Network With Embryonic Neural Cells

In today's society,more and more people are suffering from cancer all around the world.However,cancer is a very complex disease and so far there is no effective method for the therapy of cancer.In recent years,some researchers believe that cancer has crosstalk with nerves,and cancer has been proposed to be a disease of cell dedifferentiation resulting from gene dysregulation.The cancer cells have been proposed into a stem cell-like state by reprogramming the terminally differentiated cells.It is reported that cancer stem cells derived from the patients of gastric cancer and colorectal cancer can transdifferentiate into neurons including sympathetic and parasympathetic neurons and the neurons have normal physiological functions.Here,we report that cellular reprogramming make solid cancer cells differentiate into neuron-like cells when we inhibit the chromatin modification enzymes:HDACs,DNMT1,LSD 1,EZH2 by using a cocktail of the inhibitors of the four chromatin modification factors:TSA,AZA,LSD1 inhibitor,EZH2 inhibitor(TALE)or make knockdown of the chromatin modification enzymes through lentiviral infection.The resulting differentiation cells closely resemble neuron cells morphological and molecularly.The microarray analysis revealed that TALE induces solid cancer cells toward a neural differentiation.Treatment of TALE cause the loss of malignancy in solid cancer cells.The treatment cancer cells by TALE led to an obviously reduction in migration and invasion.Human umbilical vein endothelial cells(HUVECs)treated with TALE displayed stronger inhibition of tube formation,indicating the repression of TALE effect on angiogenesis.In TALE treated cells,H3K4mel,me2 and me3 were increased,H3K9me3 and H3K27me3 were decreased,H3K9ac,H3K27ac and H4K16ac were increased and DNA methylation were decreased.It means that the neuron-like cells establish a transcriptional active state by increasing chromatin active marks and reducing repressive marks.Typical mature neuron marker genes BDNF,MAP2,TUBB3,SYN1,SYP,are upregulated in the neuron-like cells induced from solid cancer cells.In addition,upregulation expression of cell-cycle inhibition genes CDKN1A,CDKN1C,CDKN2B and CDKN2D confirmed that the induced cells underwent cell cycle exit,a feature of postmitotic neurons.In addition,we confirm that most of the TPGs(tumor promoting genes)are tested to express in embryonic neural tissues during Xenopus early embryogenesis.And most of TSGs(tumor suppressor genes)are expressed in non-neural tissues.The major tumor-promoting genes or pathways are most likely to express in neural cells,including the epithelial-to-mesenchymal transition(EMT)mesenchymal marker genes,display neural-specific expression during embryonic neurulation.Whereas tumor suppressor genes,including the EMT epithelial marker gene that encodes cadherin 1(CDH1),exhibited non-neural.This correlation indicated that cancer cells and embryonic neural cells share a regulatory network,mediating both tumorigenesis and neural development.This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells.In summary,our work revealed for the first time of the approach for inducing neuron-like cells from solid cancer cells and revealed that the process was a cellular reprogramming process.In addition,we found solid cancer cells share a regulatory network with embryonic neural cells.We hope to find a new direction for the treatment of cancer through researching cancer cell differentiation.