scholarly journals The Establishment of CDK9/ RNA PolII/H3K4me3/DNA Methylation Feedback Promotes HOTAIR Expression by RNA Elongation Enhancement in Cancer

2019 ◽  
Author(s):  
Chi Hin Wong ◽  
Chi Han Li ◽  
Qifang He ◽  
Joanna Hung Man Tong ◽  
Ka-Fai To ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Transcription Elongation ◽  
Underlying Mechanism ◽  
Transcriptional Elongation ◽  
Gene Body ◽  
Gene Body Methylation ◽  
Positive Feedback Loop

SUMMARYLong non-coding RNA HOX Transcript Antisense RNA (HOTAIR) is overexpressed in multiple cancers with diverse genetic profiles, which heavily contributed to cancer progression. However, the underlying mechanism leading to HOTAIR deregulation is largely unexplored. Here, we revealed that gene body methylation promoted HOTAIR expression through enhancing the transcription elongation process in cancer. We linked up the aberrant gene body histone and DNA methylation in promoting transcription elongation via phosphorylation of Polymerase II Ser 2 by CDK7-CDK9, and elucidated the mechanism of a positive feedback loop involving CDK7, MLL1 and DNMT3A in promoting gene body methylation and overexpressing HOTAIR. To our knowledge, this is the first time to demonstrate that a positive feedback loop that involved CDK9-mediated phosphorylation of PolII and histone and gene body methylation induced robust transcriptional elongation, which heavily contributed to the upregulation of oncogenic lncRNA in cancer.

scholarly journals A Positive Feedback Loop of lncRNA MIR31HG-miR-361-3p -YY1 Accelerates Colorectal Cancer Progression Through Modulating Proliferation, Angiogenesis, and Glycolysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Tao Guo ◽  
Defeng Liu ◽  
Shihao Peng ◽  
Meng Wang ◽  
Yangyang Li
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Positive Feedback Loop ◽  
Related Proteins

BackgroundColorectal cancer (CRC) is a common malignant tumor with high metastatic and recurrent rates. This study probes the effect and mechanism of long non-coding RNA MIR31HG on the progression of CRC cells.Materials and MethodsQuantitative real-time PCR (qRT-PCR) was used to analyze the expression of MIR31HG and miR-361-3p in CRC tissues and normal tissues. Gain- or loss-of-function assays were conducted to examine the roles of MIR31HG, miR-361-3p and YY1 transcription factor (YY1) in the CRC progression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and colony formation experiment were conducted to test CRC cell proliferation. CRC cell invasion was determined by Transwell assay. The glucose detection kit and lactic acid detection kit were utilized to monitor the levels of glucose and lactate in CRC cells. The glycolysis level in CRC cells was examined by the glycolytic stress experiment. Western blot was performed to compare the expression of glycolysis-related proteins (PKM2, GLUT1 and HK2) and angiogenesis-related proteins (including VEGFA, ANGPT1, HIF1A and TIMP1) in HUVECs. The binding relationships between MIR31HG and miR-361-3p, miR-361-3p and YY1 were evaluated by the dual-luciferase reporter assay and RNA immunoprecipitation (RIP).ResultsMIR31HG was up-regulated in CRC tissues and was associated with poorer prognosis of CRC patients. The in-vitro and in-vivo experiments confirmed that overexpressing MIR31HG heightened the proliferation, growth, invasion, glycolysis and lung metastasis of CRC cells as well as the angiogenesis of HUVECs. In addition, MIR3HG overexpression promoted YY1 mRNA and protein level, and forced overexpression of YY1 enhanced MIR31HG level. Overexpressing YY1 reversed the tumor-suppressive effect mediated by MIR31HG knockdown. miR-361-3p, which was inhibited by MIR31HG overexpression, repressed the malignant behaviors of CRC cells. miR-361-3p-mediated anti-tumor effects were mostly reversed by upregulating MIR31HG. Further mechanism studies illustrated that miR-361-3p targeted and negatively regulated the expression of YY1.ConclusionThis study reveals that MIR31HG functions as an oncogenic gene in CRC via forming a positive feedback loop of MIR31HG-miR-361-3p-YY1.

scholarly journals miR-577 Regulates TGF-β Induced Cancer Progression through a SDPR-Modulated Positive-Feedback Loop with ERK-NF-κB in Gastric Cancer

2019 ◽  
Vol 27 (6) ◽  
pp. 1166-1182 ◽  
Author(s):  
Yuhao Luo ◽  
Jianhua Wu ◽  
Qianying Wu ◽  
Xiaoyin Li ◽  
Jiani Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Positive Feedback Loop

scholarly journals ACTH-Dependent Cyclic Cushing Syndrome Triggered by Glucocorticoid Excess Through a Positive-Feedback Mechanism

2018 ◽  
Vol 104 (5) ◽  
pp. 1788-1791 ◽  
Author(s):  
Yasufumi Seki ◽  
Satoshi Morimoto ◽  
Fumiko Saito ◽  
Noriyoshi Takano ◽  
Shihori Kimura ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Cushing Syndrome ◽  
Underlying Mechanism ◽  
Interesting Case ◽  
High Dose ◽  
Plasma Acth ◽  
Glucocorticoid Treatment ◽  
Positive Feedback Loop ◽  
Cortisol Levels

Abstract Context Cyclic Cushing syndrome is a rare variant of Cushing syndrome that demonstrates periodic cortisol excess. It has been thought that inhibition of a glucocorticoid positive-feedback loop is associated with remission of hypercortisolism in ACTH-dependent cyclic Cushing syndrome. However, the underlying mechanism that triggers the development of the hypercortisolism is still unknown. We observed a case of ACTH-dependent cyclic Cushing syndrome that was developed by exogenous glucocorticoids, possibly through a glucocorticoid positive-feedback loop. Case Description A 75-year-old woman had experienced cyclic ACTH and cortisol elevations six times in the previous 4 years. Her diagnosis was cyclic Cushing syndrome. During the hypercortisolemic phase, neither low-dose nor high-dose dexamethasone suppressed her plasma ACTH and cortisol levels. Daily metyrapone therapy decreased her plasma cortisol and ACTH levels during every hypercortisolemic phase. After the sixth remission of a hypercortisolemic phase, she took 25 mg of hydrocortisone for 4 weeks and developed ACTH-dependent hypercortisolemia. Treatment with 1 mg of dexamethasone gradually increased both plasma ACTH and cortisol levels over 2 weeks, resulting in the eighth hypercortisolemic phase. Treatment using a combination of dexamethasone and metyrapone did not increase plasma ACTH or cortisol level and successfully prevented development of ACTH-dependent hypercortisolism. Conclusion We present an interesting case of cyclic Cushing syndrome in which ACTH-dependent hypercortisolemic phases relapsed during exogenous glucocorticoid treatment. A glucocorticoid positive-feedback loop and endogenous glucocorticoid synthesis may play key roles in the periodicity of hypercortisolism in cyclic Cushing syndrome.

scholarly journals Diabetes-induced increased oxidative stress in cardiomyocytes is sustained by a positive feedback loop involving Rho kinase and PKCβ2

2012 ◽  
Vol 303 (8) ◽  
pp. H989-H1000 ◽  
Author(s):  
Hesham Soliman ◽  
Anthony Gador ◽  
Yi-Hsuan Lu ◽  
Guorong Lin ◽  
Girish Bankar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Contractile Function ◽  
Rho Kinase ◽  
Underlying Mechanism ◽  
Diabetic Rat ◽  
Positive Feedback Loop ◽  
Rat Hearts ◽  
Inos Inhibition

We previously reported that acute inhibition of the RhoA/Rho kinase (ROCK) pathway normalized contractile function of diabetic rat hearts, but the underlying mechanism is unclear. Protein kinase C (PKC) β2 has been proposed to play a major role in diabetic cardiomyopathy at least in part by increasing oxidative stress. Further evidence suggests that PKC positively regulates RhoA expression through induction of inducible nitric oxide synthase (iNOS) in diabetes. However, in preliminary studies, we found that inhibition of ROCK itself reduced RhoA expression in diabetic hearts. We hypothesized that there is an interaction between RhoA/ROCK and PKCβ2 in the form of a positive feedback loop that sustains their activation and the production of reactive oxygen species (ROS). This was investigated in cardiomyocytes isolated from diabetic and control rat hearts, incubated with or without cytochalasin D or inhibitors of ROCK, RhoA, PKCβ2, or iNOS. Inhibition of RhoA and ROCK markedly attenuated the diabetes-induced increases in PKCβ2 activity and iNOS and RhoA expression in diabetic cardiomyocytes, while having no effect in control cells. Inhibition of PKCβ2 and iNOS also normalized RhoA expression and ROCK overactivation, whereas iNOS inhibition reversed the increase in PKCβ2 activity. Each of these treatments also normalized the diabetes-induced increase in production of ROS. Actin cytoskeleton disruption attenuated the increased expression and/or activity of all of these targets in diabetic cardiomyocytes. These data suggest that, in the diabetic heart, the RhoA/ROCK pathway contributes to contractile dysfunction at least in part by sustaining PKCβ2 activation and ROS production via a positive feedback loop that requires an intact cytoskeleton.

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