Study On The Differentiation Of Tumor Cells Into Neuron-like Cells And Its Underlying Mechanism

Tumorigenesis,endowing the cancer cells redifferentiation potency,has been thought to result from normal active cells which have undergone misregulation of genes.Emerging evidences illustrate that solid tumor cells have capacity transdifferentiating into neural cells.But the mechanism is not well understood.Large of studies demonstrate that many epigenetic factors are involved in tumor development and play a critical role in nervous development.These epigenetic factors include Enhancer of zeste homolog 2(EZH2),DNA methyltransferase 1(DNMT1),Histone deacetylase 1(HDAC1)and Lysine(K)-specific demethylase 1A(LSD1).There is research evidence that histone modification,including H3K4me1/2/3,H3K4me1/2/3 and H3K9ac,and the presence of large amounts of DNA methylation,play a critical role in maintaining sternness of neural stem cells.The decrease of such modifications is one of the factors to promote the terminal differentiation of neural stem cells into neurons.EZH2 as an enzyme subunit of Polycomb repressive complex 2(PRC2),is a key factor to catalyze H3K27me3 and keep transcription silencing.Studies have shown that EZH2 plays a fundamental role in maintaining pluripotency of stem cell and promoting initiation,development,metabolic,drug resistance in a variety of tumors,as well as process of tumor angiogenesis.Meanwhile,EZH2 can not only catalyze histone methylation by PRC2 complex,but also has the non-classical function of post-translational modifications(PTMs)of non-histone by catalytic activity alone.Proteins such as STAT3,RORa,GATA4 are the substrate of EZH2.Based on these,EZH2 has also become a key target for tumor treatment.It is reported that the knock-down of EZH2 can facilitate the differentiation of human mesenchymal stem cells to nerve cells.Further works revealed that EZH2 plays key role in balancing self-renewal and differentiation of pluripotent stem cells in the cerebral cortex,and involves in maintaining the stemness of neurogenic astroglia in the subventricular region of the mouse brain.Abnormal DNA methylation can silence the expression of tumor suppressor genes and promote the tumorigenesis.The overexpression of DNMT1 is a main factor for the aberrant methylation of DNA in multiple tumors.Some researches elucidate that the high expression of DNMT1 in bladder cancer,hepatocellular carcinoma and gastric carcinoma can promote the expression silence of genes involved in apoptosis,DNA repair and some other cellular activities,and then keeping the malignancy of tumors.While,the dynamic activity of DNA methylation about nerve associated genes is supposed to participate neurogenesis and neural activities.Histone deacetylase family members(HDACs)can promote the expression silencing of tumor suppressor genes by synergistic action with DNA binding factors and multifunctional inhibitor complex,thus promoting the occurrence and development of tumors.In addition,HDAC1 can perform deacetylation function directly on P53 protein to maintain the malignant state of tumors.A large number of studies have been conducted in the role of HDAC family in nerve development.It has been shown that inhibition of HDACs can promote the neurotrophic specialization of nerve progenitor cells.As the first histone demethylase discovered,LSD1 plays an important role in maintaining chromatin structure and balancing gene expression.At the same time,it is also the pathogenic gene of a variety of tumors including neuroblastoma,breast cancer,liver cancer and so on.Previous studies have shown that LSD1 is involved in maintaining the sternness of mouse cerebral cortex nerve progenitor cells through the regulation of gene ATN1.In addition,LSD 1/CoREST complex has important effects on the differentiation,migration and morphogenesis of mouse nerves.It has been reported that nerve cells,especially autonomic nerve cells,play an important role in promoting migration,invasion and growth of solid tumors,such as prostate cancer,stomach cancer and colon cancer,and are an important factor for maintaining malignant tumors.At the same time,tumor cells also secrete corresponding neurotrophic factors to promote nerve growth.Experiments showed that Surgical and pharmacological ablation of nerves in gastric cancer tissue of mice could effectively inhibit tumor growth and enhance the therapeutic effect of drugs.Based on the above results,we conclude that epigenetic protein factors are highly expressed in most tumors.However,most of the current studies are limited to the single factor's influence on tumor,but synergistic effects of different factors are ignored.As a result,the current treatment of cancer has always been somewhat limited.So,it is not clear whether epigenetic proteins have synergistic effects in promoting tumor development.At the same time,the underlying mechanism of the inevitable association between tumor cells and neural stem cells remains to be elucidated.In our researches,stable knocking-down of EZH2,DNMT1,HDAC1 and LSD1 in HepG2 cells and other cancer cells resulted in the remission of malignancy,proliferation and metastasis.Combined inhibition of the four factors can intensify these effects,and the filamentous extensions resembling the axon appeared.Further experiments have confirmed the upregulation of neural-specific genes.It's worth noting that individual knockdown of EZH2 can acquire the phenotype of nerve.Deep researches found direct interaction of proteins EZH2,DNMT1,HDAC1 and LSD1 between each other,and the influence in Wnt/?-catenin pathway and TGF-? pathway.According to the reports,hyperactivation of Wnt/?-catenin pathway is an important reason for the tumorigenesis,and TGF-? pathway is a key factor to maintain the malignancy in middle and late stage of many carcinomas.Meanwhile,the two signal pathways play a role in brain development and balancing the self-renewal and differentiation of neural stem cells.We have demonstrated the expression of multiple of oncogenes in the area of Xenopus early embryonic neural development and formation.These findings hint us the general characters between tumor cells and neural stem cells,and the possibility of differentiation toward nerve by changing the epigenetic modification of tumor cells.Finally,we further studied the specific mechanism of tumor differentiation into neuron-like cells,and explained the mechanism of the interaction between the various epigenetic factors.Above all,we believe that most solid tumor cells have the properties of neural stem cells,and comprehensive alter of the key epigenetic modifications in tumor cells is an important way to inhibit the development of tumor and promote its neurogenesis.We hope these researches can provide a new approach for cancer treatment and transdifferentiation researches.