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PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy.

ABSTRACT: Prostate cancer (PCa) is one of the major malignancies affecting males' health around the world. Long noncoding RNAs (lncRNAs), a class of long transcripts, has been reported as essential regulators in tumorigenesis. IDH1 antisense RNA 1 (IDH1-AS1) is an lncRNA which can interact with genes to regulate the Warburg effect. However, function and mechanism of it in tumorigenesis of PCa remains unclear. Therefore, our current study focused on exploring the role of IDH1-AS1 in PCa tumor growth. At first, the expression of IDH1-AS1 was identified to be upregulated in PCa samples and cell lines. Mechanism associated with the upregulation of IDH1-AS1 was analyzed and demonstrated by mechanism experiments. The result suggested that PAX5 is the transcriptional activator of IDH1-AS1. Functionally, loss-of function assays revealed that silencing of IDH1-AS1 inhibited cell proliferation and induced cell apoptosis both in vitro and in vivo. Through microarray analysis and Gene ontology (GO) analysis, we determined that IDH1-AS1 can affect PCa cell autophagy by upregulating ATG5 expression. Mechanism investigation further validated that IDH1-AS1 posttranscriptionally regulated ATG5 expression by enhancing the mRNA stability of ATG5 or upregulating ATG5 by sequestering miR-216b-5p. Consequently, rescue assays demonstrated that IDH1-AS1 promoted proliferation and apoptosis in PCa via ATG5-induced autophagy. Taken together, our study elucidated the function and regulatory mechanism of IDH1-AS1, thus providing a novel biomarker for PCa.

SUBMITTER: Zhang N

PROVIDER: S-EPMC6769014 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy.

Zhang Nan N Li Zhongyi Z Bai Fuding F Zhang Shigeng S

Cell death & disease 20190930 10

Prostate cancer (PCa) is one of the major malignancies affecting males' health around the world. Long noncoding RNAs (lncRNAs), a class of long transcripts, has been reported as essential regulators in tumorigenesis. IDH1 antisense RNA 1 (IDH1-AS1) is an lncRNA which can interact with genes to regulate the Warburg effect. However, function and mechanism of it in tumorigenesis of PCa remains unclear. Therefore, our current study focused on exploring the role of IDH1-AS1 in PCa tumor growth. At fi ...[more]

PMID: 31570703

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Project description:A growing number of dysregulated long non‑coding (lnc)RNAs have been verified to serve an essential role in human prostate cancer. However, the underlying mechanisms of lncRNA MNX1 Antisense RNA 1 (MNX1‑AS1) in prostate cancer has not been explored. Therefore, the present study aimed to explore the function of MNX1‑AS1 in prostate cancer tumorigenesis and investigate the in‑depth mechanism. The expression of MNX1‑AS1, microRNA (miR)‑2113 and murine double min 2 (MDM2) in prostate cancer tissues and corresponding normal tissues were assessed by reverse transcription‑quantitative PCR. The protein expression levels of MDM2 were detected by western blotting. LNCaP and PC‑3 cells were transfected with short hairpin (sh)‑MNX1‑AS1, miR‑2113 mimics, miR‑2113 inhibitor and pCDH‑MDM2 vector using Lipofectamine® 3000. Cell proliferation, migration and invasion abilities were assessed by CCK‑8 assay, colony formation and Transwell assay, respectively. Dual luciferase reporter assay was carried out to confirm the putative targets of MNX1‑AS1 and miR‑2113. Tumor formation experiment in nude mice was applied to evaluate the tumor growth effect of MNX1‑AS1 in vivo. The expression of MNX1‑AS1 was significantly upregulated in the prostate cancer tissues and cell lines. MNX1‑AS1 knockdown suppressed the abilities of cell viability and migration and invasion in vitro and inhibited tumor growth in vivo. Additionally, luciferase reporter assay revealed that MNX1‑AS1 could target miR‑2113 and negatively interacted with miR‑2113 in prostate cancer cells. miR‑2113 directly targeted to MDM2 and negatively modulated the expression of MDM2. Rescue assays suggested that the viability, migration and invasion of impaired cells triggered by transfection with sh‑MNX1‑AS1 alone could be recovered by co‑transfection with sh‑MNX1‑AS1 + miR‑2113 inhibitor or sh‑MNX1‑AS1 + pCDH‑ MDM2 vector. The present study demonstrated that MNX1‑AS1 promoted prostate cancer progression through regulating miR‑2113/ MDM2 axis.

Project description:Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Specific metabolic features of PCa might serve as therapeutic targets for tumor radiosensitization and as biomarkers for identifying the patients most likely to respond to radiotherapy. The study aimed to characterize a potential role of glutaminase (GLS)-driven glutamine catabolism as a prognostic biomarker and a therapeutic target for PCa radiosensitization. Methods: We analyzed primary cell cultures and radioresistant (RR) derivatives of the conventional PCa cell lines by gene expression and metabolic assays to identify the molecular traits associated with radiation resistance. Relative radiosensitivity of the cell lines and primary cell cultures were analyzed by 2-D and 3-D clonogenic analyses. Targeting of glutamine (Gln) metabolism was achieved by Gln starvation, gene knockdown, and chemical inhibition. Activation of the DNA damage response (DDR) and autophagy was assessed by gene expression, western blotting, and fluorescence microscopy. Reactive oxygen species (ROS) and the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) were analyzed by fluorescence and luminescence probes, respectively. Cancer stem cell (CSC) properties were investigated by sphere-forming assay, CSC marker analysis, and in vivo limiting dilution assays. Single circulating tumor cells (CTCs) isolated from the blood of PCa patients were analyzed by array comparative genome hybridization. Expression levels of the GLS1 and MYC gene in tumor tissues and amino acid concentrations in blood plasma were correlated to a progression-free survival in PCa patients. Results: Here, we found that radioresistant PCa cells and prostate CSCs have a high glutamine demand. GLS-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as GLS and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Conclusions: Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

Dataset Information

PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy.

Publications

PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy.

Similar Datasets

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