ERp29 forms a feedback regulation loop with microRNA-135a-5p and promotes progression of colorectal cancer

Huang, Jiaoling; Jing, Mengxia; Chen, Xixi; Gao, Yuanqi; Hua, Huiying; Pan, Chuyue; Wu, Jing; Wang, Xinqiong; Chen, Xuehua; Gao, Yujing; Xu, Chao; Li, Pu

doi:10.1038/s41419-021-04252-z

Cited by 7 publications

(7 citation statements)

References 59 publications

(57 reference statements)

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“…Furthermore, the combined decitabine and PBA treatment repressed the ER stress response genes ERP29 and PDIA3. Importantly, ERP29 is frequently deregulated in cancer and forms a feedback loop with microRNA-135a-5p to promote progression of colorectal cancer [ 69 ], while protein disulfide isomerase family A member 3 (alias ERP57) modulates folding of glycoproteins and stimulates cell proliferation via c-Myc, PLK1 and the AKT pathway [ 70 ]. Moreover, PDIA3 promotes cancer cell proliferation and is associated with poor prognosis in hepatocellular carcinoma [ 71 ], while the helicase HELLS functions in DNA-strand separation and replication repair.…”

Section: Resultsmentioning

confidence: 99%

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

2023

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Background Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density. Results Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients. Conclusion The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.

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Section: Resultsmentioning

confidence: 99%

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

2023

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“…Although a high level of ERp29 expression can inhibit CNV in vivo, the effect of its overexpression on other cells in the eye as well as its safety with respect to visual function still require further research. In addition, ERp29 is highly expressed in various tumor tissues, and some researchers have identified ERp29 as a carcinogenesis-related gene [60,61]. In addition to the upregulation of ERp29 expression in tumor tissues, the expression of ERp29 can also be upregulated after ionizing radiation [62,63].…”

Section: Discussionmentioning

confidence: 99%

ERp29 Attenuates Nicotine-Induced Endoplasmic Reticulum Stress and Inhibits Choroidal Neovascularization

Lu,

Xie,

Huang

et al. 2023

IJMS

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Nicotine-induced endoplasmic reticulum (ER) stress in retinal pigment epithelium (RPE) cells is thought to be one pathological mechanism underlying age-related macular degeneration (AMD). ERp29 attenuates tobacco extract-induced ER stress and mitigates tight junction damage in RPE cells. Herein, we aimed to further investigate the role of ERp29 in nicotine-induced ER stress and choroidal neovascularization (CNV). We found that the expression of ERp29 and GRP78 in ARPE-19 cells was increased in response to nicotine exposure. Overexpression of ERp29 decreased the levels of GRP78 and the C/EBP homologous protein (CHOP). Knockdown of ERp29 increased the levels of GRP78 and CHOP while reducing the viability of ARPE-19 cells under nicotine exposure conditions. In the ARPE-19 cell/macrophage coculture system, overexpression of ERp29 decreased the levels of M2 markers and increased the levels of M1 markers. The viability, migration and tube formation of human umbilical vein endothelial cells (HUVECs) were inhibited by conditioned medium from the ERp29-overexpressing group. Moreover, overexpression of ERp29 inhibits the activity and growth of CNV in mice exposed to nicotine in vivo. Taken together, our results revealed that ERp29 attenuated nicotine-induced ER stress, regulated macrophage polarization and inhibited CNV.

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“…MicroRNAs (miRNAs) are crucial post-transcriptional regulators in physiological and pathological environments [6]. Studies have shown that miRNA is rapidly degraded by binding to the 3′-untranslated region (3′-UTR) of the target gene to affect the expression of the gene [7]. What is more, miRNAs are stable in tissue specimens, highlighting their underlying utility as prognostic biomarkers in different diseases, such as cardiovascular disease and inflammation [8,9].…”

Section: Introductionmentioning

confidence: 99%

miR-135a Mediates Mitochondrial Oxidative Respiratory Function through SIRT1 to Regulate Atrial Fibrosis

Ding,

Zeng,

Xia

et al. 2024

Cardiology

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Introduction: This study aimed to explore the function of miR-135a in the progress of atrial fibrosis and the mechanism of miR-135a/SIRT1 (sirtuin 1) in human cardiac fibroblasts and mouse cardiac fibroblasts (MCFs) mediating the regulation of atrial fibrosis by mitochondrial oxidative respiration function. Methods: Using Ang II (angiotensin II) to induce fibrosis in HCFs (human corneal fibroblasts) and MCF (Michigan Cancer Foundation, MCF) cells in vitro, the miRNA-seq results of previous studies were validated. Proliferative and invasive ability of HCFs and MCFs was detected by Cell Counting Kit-8 assay (CCK-8) and scratch experiment after overexpressing miR-135a in HCFs and MCF cells. Protein and mRNA expression was tested using Western blot and qPCR. The target of miR-135a was verified as SIRT1 by a luciferase reporter assay and the activities of the mitochondrial respiratory enzyme complexes I, II, III, and IV were determined colorimetrically. The activities of malondialdehyde, reactive oxygen species, and superoxide dismutase in cells were detected with enzyme-linked immunosorbent assay (ELISA). Results: miR-135a expression was elevated in HCFs and MCFs cells in the Ang II group than control group. Overexpression of miR-135a could promote the proliferation, migration, oxidative stress, as well as fibrosis of cardiac fibroblasts and suppresses mitochondrial activity. In addition, we found SIRT1 was a target gene of miR-135a. What is more, the findings showed miR-135a promoted fibrosis in HCFs and MCFs cells acting through regulation of SIRT1. Conclusions: miR-135a mediates mitochondrial oxidative respiratory function through SIRT1 to regulate atrial fibrosis.

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ERp29 forms a feedback regulation loop with microRNA-135a-5p and promotes progression of colorectal cancer

Cited by 7 publications

References 59 publications

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas

ERp29 Attenuates Nicotine-Induced Endoplasmic Reticulum Stress and Inhibits Choroidal Neovascularization

miR-135a Mediates Mitochondrial Oxidative Respiratory Function through SIRT1 to Regulate Atrial Fibrosis

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