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ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer.

ABSTRACT: Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship between ER stress-related ATF signaling and CIP2A. We found that CIP2A expression was positively correlated with ATF6 expression by analyzing publicly available RNA sequence data of patients with colorectal cancer (The Cancer Genome Atlas, TCGA). In addition, we demonstrated that tunicamycin-induced ER stress in vitro upregulated ATF6 and CIP2A. Mechanistically, we found that ATF6 directly bound to the CIP2A promoter and induced CIP2A gene expression, which contributed to colon cancer cell survival. Furthermore, knockdown of CIP2A reduced the viability of cells under ER stress. Most importantly, immunohistochemical analysis of a tissue microarray from a colon cancer patient cohort showed that higher expression levels of ATF6 and CIP2A were associated with a trend toward poor prognosis. Taken together, our results show that ER stress-related ATF6 upregulates CIP2A and contributes to the prognosis of colon cancer. Targeting CIP2A may disrupt ER stress-mediated colon cancer cell survival and thus improve the prognosis of patients with colon cancer.

SUBMITTER: Liu CY

PROVIDER: S-EPMC6166000 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer.

Liu Chun-Yu CY Hsu Chia-Chi CC Huang Tzu-Ting TT Lee Chia-Han CH Chen Ji-Lin JL Yang Shung-Haur SH Jiang Jeng-Kai JK Chen Wei-Shone WS Lee Kuan-Der KD Teng Hao-Wei HW

Molecular oncology 20180820 10

Endoplasmic reticulum (ER) stress is an adaptive response to various stress conditions and plays emerging roles in cancer. Activating transcription factor 6 (ATF6), one of the three major ER stress transducers, has been shown to contribute to chemoresistance by altering cancer cell survival. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogene, and its expression has been correlated with the prognosis of patients with cancer. In this study, we aimed to explore the relationship be ...[more]

PMID: 30063110

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Project description:Currently, the occurrence and mortality rate of cervical cancer is high, particularly in low-to-middle-income countries. Therefore, the development of novel diagnostic and treatment strategies for cervical cancer is urgently required. The aim of the present study was to assess the prognostic significance of fibronectin type III domain containing 3B (FNDC3B) expression in patients with cervical cancer and to determine the underlying mechanism of FNDC3 in tumor development. Analysis of the ONCOMINE database revealed that FNDC3B was significantly upregulated in cervical cancer tissue compared with normal tissue. Additionally, FNDC3B expression data and the clinical characteristics of patients with cervical cancer were obtained from the cBioPortal database. Correlations between FNDC3B expression and overall survival were subsequently investigated. The results revealed that increased FNDC3B expression was significantly correlated with a lower overall survival in patients with cervical cancer. A co-expression network was subsequently constructed to elucidate the function of FNDC3B in cervical cancer. Co-expression genes for FNDC3B were obtained from the cBioPortal database and were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The results demonstrated that the genes were enriched in pathways associated with migration, invasion, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Furthermore, immunofluorescence results obtained from the Human Protein Atlas revealed that the FNDC3B protein was localized to the ER. The results revealed that upregulated FNDC3B expression may be a biomarker for poor prognosis for patients with cervical cancer. Additionally, the results revealed that FNDC3B may serve an oncogenic role in cancer development via ER stress, UPR, cell migration and invasion. However, further studies are required to determine the exact molecular mechanism of FNDC3B in the development of cervical cancer and to assess its potential as a novel therapeutic target for the treatment of this disease.

Project description:Background & aimsN-nicotinamide methyltransferase (NNMT) is emerging as an important enzyme in the regulation of metabolism. NNMT is highly expressed in the liver. However, the exact regulatory mechanism(s) underlying NNMT expression remains unclear and its potential involvement in alcohol-related liver disease (ALD) is completely unknown.MethodsBoth traditional Lieber-De Carli and the NIAAA mouse models of ALD were employed. A small-scale chemical screening assay and a chromatin immunoprecipitation assay were performed. NNMT inhibition was achieved via both genetic (adenoviral short hairpin RNA delivery) and pharmacological approaches.ResultsChronic alcohol consumption induces endoplasmic reticulum (ER) stress and upregulates NNMT expression in the liver. ER stress inducers upregulated NNMT expression in both AML12 hepatocytes and mice. PERK-ATF4 pathway activation is the main contributor to ER stress-mediated NNMT upregulation in the liver. Alcohol consumption fails to upregulate NNMT in liver-specific Atf4 knockout mice. Both adenoviral NNMT knockdown and NNMT inhibitor administration prevented fatty liver development in response to chronic alcohol feeding; this was also associated with the downregulation of an array of genes involved in de novo lipogenesis, including Srebf1, Acaca, Acacb and Fasn. Further investigations revealed that activation of the lipogenic pathway by NNMT was independent of its NAD+-enhancing action; however, increased cellular NAD+, resulting from NNMT inhibition, was associated with marked liver AMPK activation.ConclusionsER stress, specifically PERK-ATF4 pathway activation, is mechanistically involved in hepatic NNMT upregulation in response to chronic alcohol exposure. Overexpression of NNMT in the liver plays an important role in the pathogenesis of ALD.Lay summaryIn this study, we show that nicotinamide methyltransferase (NNMT) - the enzyme that catalyzes nicotinamide degradation - is a pathological regulator of alcohol-related fatty liver development. NNMT inhibition protects against alcohol-induced fatty liver development and is associated with suppressed de novo lipogenic activity and enhanced AMPK activation. Thus, our data suggest that NNMT may be a potential therapeutic target for the treatment of alcohol-related liver disease.

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ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer.

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ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer.

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