Selective inhibitors epigenetically modify and eradicate tumor‐initiating stem‐like cells through downregulating microRNA 22‐mediated TET induction and apoptosis
Keigo MachidaChia‐Lin NONE ChenDinesh Babu Uthaya KumarSuresh K. SwaminathanSamuel W. FrenchJayanth Panyam
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A critical barrier to improved cancer therapy is the recurrence of drug‐resistant tumors expanded from tumor‐initiating stem‐like cells (TICs). Discovery of a drug that specifically targets the TIC population is critical for effective treatment. We first performed drug screening on TICs for the identification of cell‐type specific drugs and found that all‐trans retinoic acid (ATRA) specifically inhibited cell viability. Additionally, transduction of human TICs with a lentivirus Nanog‐GFP reporter was used to perform high‐throughput screening for Nanog‐inhibitory drugs. HDAC inhibitor (SAHA), among several candidates, suppressed Nanog expression. Three high‐throughput screenings identified the best combination of repurposed FDA‐approved drugs (ATRA and SAHA). Moreover, combination of RA with SAHA synergistically reduced Nanog expression and inhibited the self‐renewal abilities of TICs resulting in apoptosis in vitro and in vivo. Genome‐wide transcriptome analysis by using of RNA‐seq showed that combined treatment reduced microRNA‐22, which induced phosphatase and tensin homolog (PTEN) and ten‐eleven translocation (TET). PTEN‐mediated FOXO activation promotes BIM‐mediated apoptosis. TET induction demethylates p53‐binding sites within the Nanog promoter proximal region. The drug combination epigenetically altered DNA methylation of Nanog promoter leading to inactivation of Nanog in TICs. Taken together, ATRA and SAHA may serve as a novel strategy for HCC treatment. Support or Funding Information This project was supported by NIH research grants R01AA018857, P50AA011999 (Southern California Research Center for ALPD and Cirrhosis, pilot project, program, animal core, morphology core), Lee‐Summer‐Project funding, P30DK048522 (USC Research Center for Liver Diseases, pilot project program), Non‐Parenchymal Liver Cell Core (R24AA012885) and UO‐021898. This research was also supported by a Research Scholar Grant (RSG‐12‐177‐01‐MPC); pilot funding from American Cancer Society (IRG‐58‐007‐48); The Cell and Tissue Imaging Core ‐ USC Research Center for Liver Diseases (P30 DK048522).Keywords:
Homeobox protein NANOG
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PTEN(phosphatase and tensin homolog deleted on chromosome ten)is phosphatase specificity and can inhibit oncogenesis.The mutation and loss of PTEN is the oncogenesis basis of all kinds of tumor,including urinary system tumor.Studies show that mutation and loss of PTEN,which can lead to the dysfunction of tumor suppress,induced oncogenesis of renal cell carcinoma,bladder carcinoma and prostatic carcinoma,revealling that PTEN can inhibit tumorigenesis of urnary system.But the detail of the mutation and loss of PTEN and how PTEN inhibit tumorigensis are still unclear,further study is warranted.
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Phosphatase and tensin homolog deleted on chromosome ten(PTEN),one of the mostly investigated tumor suppressor genes,has a close correlation with tumorigenesis.The activation of PI3K-AKT pathway caused by abnormal PTEN is one of the major mechanisms underlying tumor occurrence.Therefore,PTEN regulation is important for uncovering new mechanisms of tumor occurrence and establishing novel therapeutic strategies.The cellular PTEN regulations including transcriptional regulation,post-transcriptional modulation,post-translation modification and protein-protein interaction are reviewed in this paper.
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Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is widely known as a tumor suppressor gene. It is located on chromosome 10q23 with 200 kb, and has dual activity of both protein and lipid phosphatase. In addition, as a targeted gene in multiple pathways, PTEN has a variety of physiological activities, such as those regulating the cell cycle, inducing cell apoptosis, and inhibiting cell invasion, etc. The PTEN gene have been identified in many kinds of cancers due to its mutations, deletions and inactivation, such as lung cancer, liver cancer, and breast cancer, and they are closely connected with the genesis and progression of cancers. To a large extent, the tumor suppressive function of PTEN is realized through its inhibition of the PI3K/AKT signaling pathway which controls cells apoptosis and development. In addition, PTEN loss has been associated with the prognosis of many cancers, such as lung cancer, liver cancer, and breast cancer. PTEN gene is related to many cancers and their pathological development. On the basis of a large number of related studies, this study describes in detail the structure, regulation, function and classical signal pathways of PTEN, as well as the relationship between various tumors related to PTEN. In addition, some drug studies targeting PTEN/PI3K/AKT/mTOR are also introduced in order to provide some directions for experimental research and clinical treatment of tumors.
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The expression pattern of tumor suppressor gene phosphatase and tensin homolog deleted on chromosome ten (PTEN) and phosphatase and tensin homolog deleted on chromosome ten/phosphatidylinositol3-kinase/protein kinase B (PTEN/PI3K/AKT) cell signaling pathway in renal cell carcinoma (RCC) were investigated in children. A total of 5 cases of RCC (observation group) in children and 10 cases of benign kidney tumor (control group) diagnosed by pathological examinations were included to obtain tumor samples. Expression of PTEN mRNA was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The protein expression of PTEN, PI3K and AKT was detected by western blotting; relationships between the expression level of PTEN mRNA and the clinical features of RCC were analyzed. It turned out that expression level of PTEN mRNA in the observation group was significantly lower than that in the control group. The protein expression levels of PTEN, PI3K and AKT were significantly lower in the observation group than in the control group (P<0.05). The expression level of PTEN mRNA decreased with the increased clinical stage of RCC (P<0.05), and was not related to sex, age and maximum tumor diame-ter (P>0.05). The results showed that downregulation of the tumor suppressor gene PTEN expression and the inhibition of PTEN/PI3K/AKT cell signaling pathway may be involved in the occurrence and development of RCC in children.
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PTEN(Phosphatase and Tensin Homology deleted from Chromosome ten),a putative antioncogene,encodes a PTEN protein that has a dual specificity phosphatase activity with both protein phosphatase and lipid phosphatase,which regulates a variety of molecules through inhibiting the PI3K/Akt signaling pathway.Recently,some scholars dedicate to the modulation of PTEN,which demonstrates that PTEN can be regulated by multiple factors at the level of gene and protein.This review briefly summarizes up-to-date information about the modulation of PTEN and its mechanisms.
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Objective To investigate whether the expression of phosphatase and tensin homolog deleted on chromosome ten( PTEN) is involved in the initiation and progression of non-smallcell lung carcinoma( NSCLC). Methods The expression of PTEN was detected in 45 paired NSCLC tumor and adjacent normal tissues by immunohistochemistry. Results The positive expression rates of PTEN in NSCLC tumor and normal tissues were 31. 1% and 66. 7% respectively,the difference was statistically significant( P = 0. 001). PTEN expressions correlated with the differentiation of the tumor( P = 0. 000). Conclusion Lack of PTEN expression may be involved in the initiation and progression of NSCLC.
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