Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway

Huang, Yu-Nan; Chiang, Shang-Lun; Lin, Yi-Chun; Liu, Su-Ching; Li, Yen-Hsien; Liao, Yu-Chen; Lee, Maw-Rong; Su, Pen‐Hua; Tsai, Fuu‐Jen; Hung, Hao-Chun; Wang, Chung-Hsing

doi:10.3390/ijms22041720

Cited by 15 publications

(9 citation statements)

References 44 publications

(50 reference statements)

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“…Here, the conversion from pyruvate to lactate, which is catalyzed by lactate dehydrogenase (LDH) proteins including the androgen receptor target LDHA1 presents a critical step ( 39 ). Current evidence, gathered primarily from studies on beta-cells in pancreatic islets, suggests that LDH release is reduced in the absence of IRAK1 ( 40 ). In cell culture and xenograft tumor models, gain of IRAK1 promotes tumorigenic growth and metastasis of breast, head neck, and hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

Schagdarsurengin

Breiding²,

Loose³

et al. 2022

Front. Oncol.

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The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed in vitro cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas. We focused on key effectors of TLR signaling, the Myddosome-complex components IRAK1, IRAK4 and MYD88 (myeloid differentiation primary response 88), and TRAF6 (tumor-necrosis-factor receptor associated factor 6). In PCa, IRAK1-mRNA was specifically enriched in luminal epithelial cells, representing 57% of all cells, whereas IRAK4 and MYD88 were predominantly expressed in leukocytes, and TRAF6, in endothelial cells. Compared to NOR, only IRAK1 was significantly overexpressed in PCa (Benjamini-Hochberg adjusted p<2x10-8), whereas the expression of IRAK4, MYD88, and TRAF6 was unchanged in PCa, and IRAK1-expression was inversely correlated with a specific differentially methylated region (IRAK1-DMR) within a predicted promoter region enriched for H3K27ac (Spearman correlation r<-0.36; Fisher’s test, p<10-10). Transcription factors with high binding affinities in IRAK1-DMR were significantly enriched for canonical pathways associated with viral infection and carcinogenic transformation in the Kyoto Encyclopedia of Gene and Genomes analysis. DU145 cells, exhibiting hypermethylated IRAK1-DMR and low IRAK1-expression, reacted with 4-fold increased IRAK1-expression upon combined treatment with 5-aza-2-deoxycytidine and trichostatin A, and were unresponsive to infection with the uropathogenic Escherichia coli strain UTI89. In contrast, PC3 and LNCaP cells, exhibiting hypomethylated IRAK1-DMR and high endogenous IRAK1-mRNA levels, responded with strong activation of IRAK1-expression to UTI89 infection. In summary, exclusive overexpression of IRAK1 was observed in luminal epithelial cells in PCa, suggesting it has a role in addition to Myddosome-dependent TLR signaling. Our data show that the endogenous epigenetic status of PCa cells within IRAK1-DMR is decisive for IRAK1 expression and should be considered as a predictive marker when selective IRAK1-targeting therapies are considered.

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Section: Discussionmentioning

confidence: 99%

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

Schagdarsurengin

Breiding²,

Loose³

et al. 2022

Front. Oncol.

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“…The downregulation of LDHA could significantly improve DM's glucose metabolism [ 52 ]. Inhibition of LDHA decreased reactive oxygen species production, reduced lactate secretion, and rescued beta-cell apoptosis [ 53 ]. Our results showed that reduced expression of miR-489 in GF group could increase the apoptosis index as determined by flow cytometry in HEK-293 cell.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Antagonizes Glucose Fluctuation-Induced Renal Injury by Inhibiting Aerobic Glycolysis via the miR-489/LDHA Pathway

Xiao-mei

Zhang

Huang

et al. 2021

Mediators of Inflammation

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It has been considered that glucose fluctuation (GF) plays a role in renal injury and is related to diabetic nephropathy (DN) development. But the mechanism is still unclear. Aerobic glycolysis has become a topical issue in DN in recent years. There is an internal connection between GF, aerobic glycolysis, and DN. Curcumin (Cur) is a principal curcuminoid of turmeric and possesses specific protective properties in kidney functions. Cur also participates in the regulation of aerobic glycolysis switch. In this study, we first measured the levels of aerobic glycolysis and evaluated Cur’s inhibitory ability in a cell model of HEK-293 under the condition of oscillating high glucose. The results indicated that GF exacerbated inflammation injury, oxidative stress, and apoptosis in HEK-293 cell, while Cur alleviated this cytotoxicity induced by GF. We found that GF increased aerobic glycolysis in HEK-293 cells and Cur presented a dose-dependent weakening effect to this exacerbation. Next, we built a panel of 17 miRNAs and 8 lncRNAs that were previously reported to mediate the Warburg effect. Our RT-qPCR results indicated that GF reduced the miR-489 content in the HEK-293 cell model and Cur could prevent this downregulation. Then, we planned to explore the character of miR-489 in Cur-triggered attenuation of the Warburg effect under GF condition. Our findings presented that Cur prevented GF-triggered aerobic glycolysis by upregulating miR-489 in HEK-293 cells. Next, we choose the miR-489/LDHA axis for further investigation. We confirmed that Cur prevented GF-triggered aerobic glycolysis via the miR-489/LDHA axis in HEK-293 cells. In conclusion, this study presented that Cur prevented GF-triggered renal injury by restraining aerobic glycolysis via the miR-489/LDHA axis in the HEK-293 cell model.

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“…lncRNA SRA was reported [ 41 ] to be overexpressed in the plasma samples of 25 patients with T1D as well as in CD4+ regulatory T cells (Tregs) induced with high glucose in the CD4+ MOLT4 human T lymphoblast cell line. lncRNA SRA modulates the expression of miR-146b, which is downstream of interleukin-1 receptor-associated kinase 1 (IRAK1)/protein kinase B (AKT)/S6 Kinase 1 (S6K1) signaling.…”

Section: Dysregulated Human Ncrnas In Diabetesmentioning

confidence: 99%

Current Insights into miRNA and lncRNA Dysregulation in Diabetes: Signal Transduction, Clinical Trials and Biomarker Discovery

Pandey¹,

Ajgaonkar²,

Jadhav³

et al. 2022

Pharmaceuticals

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Diabetes is one of the most frequently occurring metabolic disorders, affecting almost one tenth of the global population. Despite advances in antihyperglycemic therapeutics, the management of diabetes is limited due to its complexity and associated comorbidities, including diabetic neuropathy, diabetic nephropathy and diabetic retinopathy. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are involved in the regulation of gene expression as well as various disease pathways in humans. Several ncRNAs are dysregulated in diabetes and are responsible for modulating the expression of various genes that contribute to the ‘symptom complex’ in diabetes. We review various miRNAs and lncRNAs implicated in diabetes and delineate ncRNA biological networks as well as key ncRNA targets in diabetes. Further, we discuss the spatial regulation of ncRNAs and their role(s) as prognostic markers in diabetes. We also shed light on the molecular mechanisms of signal transduction with diabetes-associated ncRNAs and ncRNA-mediated epigenetic events. Lastly, we summarize clinical trials on diabetes-associated ncRNAs and discuss the functional relevance of the dysregulated ncRNA interactome in diabetes. This knowledge will facilitate the identification of putative biomarkers for the therapeutic management of diabetes and its comorbidities. Taken together, the elucidation of the architecture of signature ncRNA regulatory networks in diabetes may enable the identification of novel biomarkers in the discovery pipeline for diabetes, which may lead to better management of this metabolic disorder.

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Long, Noncoding RNA SRA Induces Apoptosis of β-Cells by Promoting the IRAK1/LDHA/Lactate Pathway

Cited by 15 publications

References 44 publications

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

Interleukin-1 receptor associated kinase 1 (IRAK1) is epigenetically activated in luminal epithelial cells in prostate cancer

Curcumin Antagonizes Glucose Fluctuation-Induced Renal Injury by Inhibiting Aerobic Glycolysis via the miR-489/LDHA Pathway

Current Insights into miRNA and lncRNA Dysregulation in Diabetes: Signal Transduction, Clinical Trials and Biomarker Discovery

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