Cancer Cell . . . A new approach to prostate cancer treatment: metabolic pathways and epigenetic swords.

Prostate cancer remains the leading cause of cancer deaths in men worldwide.although the prognosis of patients with non metastatic prostate cancer is good, the 5-year survival rate of patients with metastatic prostate cancer is less than 30% [1].in order to find a more effective treatment for prostate cancer, on July 2, 2020, Qin Jun research group of Shanghai Institute of nutrition and health, Chinese Academy of Sciences, Jiangjun research group of Daping Hospital of Chongqing Military Medical University and Wang Xiaoming of Nanjing Medical University published a paper entitled "setd2 restrictions prostate cancer metastasis by integrating EZH2 and AMPK signaling" in cancer cell Pathways revealed the regulatory role of ampk-setd2-ezh2 signal axis in prostate cancer, and provided a possible reference for the treatment of prostate cancer.histone methyltransferases (HMTS) and demethylase are involved in prostate cancer metastasis [2].methyltransferase EZH2 is responsible for the modification of inhibitory H3K27me3, which enables tumor cells to acquire invasive characteristics [3].in mammals, setd2 is a methyltransferase catalyzing h3k36me3, and mutations in setd2 gene are widely present in a variety of tumors including prostate cancer [4].studies have found that setd2 regulates genomic instability, RNA processing and intragene transcription initiation through histone H3K36 methylation [5,6].h3k36me2 / 3 and h3k27me2 / 3 modified Nematoda, myeloma and mouse oocytes were mutually exclusive [7-9].however, little is known about the methylation of setd2 in non histone substrates, and the relationship between setd2 and EZH2 and its role in prostate cancer are not clear.in order to analyze the role of setd2 and EZH2 in prostate cancer, the authors compared the levels of h3k36me3 / setd2 and H3K27me3 / EZH2 in non metastatic prostate cancer mouse model PTEN - / -, and metastatic prostate cancer mouse model PTEN - / -; Trp53 - / - (Fig. 1). It was found that the expression of seh3h2 in the prostate of mice with the expression level of seh3h3h3br / > was significantly higher than that of the control group (P < 0.05).furthermore, the authors hope to evaluate the function of setd2 in prostate cancer. After knockdown of setd2 by lentiviral vector mediated short hairpin RNA, we found that the size and proliferation of PTEN - / - mice were significantly increased.studies have shown that the expression of setd2 in invasive tumors will be down regulated [10]. After overexpression of setd2 by crispra in mouse model of metastatic prostate cancer, it was found that the overexpression of setd2 caused organoid death.these results indicate that setd2 plays a key role in prostate cancer.Figure 1: comparison of h3k36me3 / setd2 and H3K27me3 / EZH2 levels in different prostate cancer mouse models. Further, the authors wanted to know the function of setd2 in vivo, so they specifically knocked out setd2 in prostate epithelial cells in vivo.setd2 - / - mice showed obvious developmental malformation and multiple low-grade prostatic intraepithelial neoplasia.however, the authors found that setd2 knockout alone was not enough to drive prostate cancer.when the authors knocked down one copy of PTEN on the basis of setd2 - / - mice, their lifespan was significantly reduced due to bladder outlet obstruction and hydronephrosis.these results suggest that setd2 knockout can accelerate the progression of prostate cancer and promote the metastasis of prostate cancer.how does setd2 knockout induce prostate cancer metastasis? After analyzing the gene expression of PTEN + / -, setd2 - / - and PTEN + / - mice, we found that the genes related to EZH2 and H3K27me3 signal transduction were significantly enriched in all the differentially expressed genes.in PTEN + / -; setd2 - / - mice, simultaneous knockdown of EZH2 slowed the progression of prostate cancer. The deletion ofsetd2 accelerates the occurrence of prostate cancer in an EZH2 dependent manner.in order to further identify the relationship between setd2 and EZH2, the authors first wanted to know whether EZH2 is a non histone substrate of setd2.through identification, the authors found that setd2 can specifically interact with EZH2 both in vivo and in vitro.by using pan methylated antibodies, the authors found that EZH2 methylation could be detected when setd2 was overexpressed.the authors found that k735, a conserved lysine residue in EZH2, could be directly methylated by setd2. Through a series of biochemical experiments, the authors were surprised to find that k735me1 induced by setd2 could promote the recognition of Smurf2 E3 ligase and degrade EZH2.moreover, the authors found that ezh2-k735me1 is very important for the progression of prostate cancer by using the mouse endogenous knock in mutant ez2k735r.after the mutation of the methylation site, ezh2k735r is not sensitive to the methylation of setd2, PTEN - / -; ezh2k735r will develop into a highly invasive cancer.in order to find the upstream signal pathway regulating the expression of setd2, the authors conducted a chemical screening in cells.in this screening, the authors found that the expression of setd2 was positively regulated by AMPK, which regulated the expression of setd2 in a FoxO3 dependent manner.AMPK agonist metformin can stimulate k735me1. The authors want to know whether metformin can affect the occurrence of prostate cancer.the authors found that metformin induced setd2 expression and reduced EZH2 and H3K27me3 levels in PTEN - / - organs.in order to further strengthen the effect of metformin, the authors treated the explants from patients with prostate cancer with metformin, and found that the conclusion was similar.Fig. 2 the regulatory role of ampk-setd2-ezh2 signaling pathway in prostate cancer. In general, this work identified the role of setd2-ezh2-k735me1 in inhibiting prostate cancer metastasis, and identified a complete regulatory axis of ampk-setd2-ezh2 signal pathway (Fig. 2). Drug intervention based on this signaling pathway is expected to treat prostate patients and provide better prognosis 。 original link: references 1. Siegel, R. L., Miller, K. D. & amp; Jemal, A. cancer statistics, 2017. CA: a cancer journal for clinicians 67, 7-30, doi:10.3322/caac.21387 (2017).2. Kim, T. 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