ATF3 suppresses ESCC via downregulation of ID1

Li, Jian; Yang, Zishan; Chen, Zhiuguo; Bao, Yonghua; Zhang, Huijuan; Fang, Xing; Yang, Wancai

doi:10.3892/ol.2016.4832

Cited by 14 publications

(15 citation statements)

References 42 publications

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“…These ndings were supported by analysis of data in public databases, including TCGA and GEO. Furthermore, consistent with our results, IFI6 overexpression is implicated in multiple malignant diseases [22,44,45], and the increase in ATF3 expression was associated with a favorable prognosis in patients with ESCC [46,47].…”

Section: Discussionsupporting

confidence: 91%

IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

Liu

et al. 2020

Preprint

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Abstract Background: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal forms of adult cancer with poor prognosis. Substantial evidence indicates that reactive oxygen species (ROS) are important modulators of aggressive cancer behavior. However, the mechanism by which ESCC cells integrate redox signals to modulate carcinoma progression remains elusive. Methods: The expression of interferon alpha inducible protein 6 (IFI6) in clinical ESCC tissues and cell lines was detected by RT-PCR and Western blotting. The correlation between IFI6 expression levels and aggressive ESCC disease stage was examined by immunohistochemistry. Bioinformatic analysis was conducted to explore the potential function of IFI6 in ESCC. ESCC cell lines stably depleted of IFI6 and ectopically expressing IFI6 were established using lentiviruses expressing shRNAs and an IFI6 expression plasmid, respectively. The effects of IFI6 on ESCC cells were determined by cell-based analyses, including EdU assay, apoptotic assay, cellular and mitochondria-specific ROS detection, seahorse extracellular flux, and mitochondrial calcium flux assays. Blue native-polyacrylamide gel electrophoresis was used to determine mitochondrial supercomplex assembly. Transcriptional activation of NADPH oxidase 4 (NOX4) via ATF3 was confirmed by dual luciferase assay. In vivo tumor growth was determined in mouse xenograft models. Results: We find that the expression of IFI6, an IFN-stimulated gene localized in the inner mitochondrial membrane, is markedly elevated in ESCC patients and a panel of ESCC cell lines. High IFI6 expression correlates with aggressive disease phenotype and poor prognosis in ESCC patients. IFI6 depletion suppresses proliferation and induces apoptosis by increasing ROS accumulation. Mechanistically, IFI6 ablation induces mitochondrial calcium overload by activating mitochondrial Ca 2+ uniporter and subsequently ROS production. Following IFI6 ablation, mitochondrial ROS accumulation is also induced by mitochondrial supercomplex assembly suppression and oxidative phosphorylation dysfunction, while IFI6 overexpression produces the opposite effects. Furthermore, energy starvation induced by IFI6 inhibition drives endoplasmic reticulum stress through disrupting endoplasmic reticulum calcium uptake, which upregulates NOX4-derived ROS production in an ATF3-dependent manner. Finally, the results in xenograft models of ESCC further corroborate the in vitro findings. Conclusion: Our study unveils a novel redox homeostasis signaling pathway that regulates ESCC pathobiology and identifies IFI6 as a potential druggable target in ESCC.

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Section: Discussionsupporting

confidence: 91%

IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

Liu

et al. 2020

Preprint

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“…ATF3 is a well-characterized, known repressor of ID1 expression. 24 It will be interesting to determine if UBR5 destabilizes ATF3. It is equally possible that loss of UBR5 leads indirectly to the loss of a positively acting transcription factor that controls ID1/ID3 expression.…”

Section: Discussionmentioning

confidence: 99%

Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response

Song

Wang

et al. 2020

OncoImmunology

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UBR5 is a nuclear phosphoprotein of obscure functions. Clinical analyses reveal that UBR5 amplifications and overexpression occur in over 20% cases of human breast cancers. Breast cancer patients carrying UBR5 genetic lesions with overexpression have significantly reduced survival. Experimental work in vitro and in vivo demonstrates that UBR5, functioning as an oncoprotein, plays a profound role in breast cancer growth and metastasis. UBR5 drives tumor growth largely through paracrine interactions with the immune system, particularly through inhibiting the cytotoxic response mediated by CD8 + T lymphocytes, whereas it facilitates metastasis in a tumor cell-autonomous manner via its transcriptional control of key regulators of the epithelial-mesenchymal transition, ID1 and ID3. Furthermore, simultaneous targeting of UBR5 and PD-L1 yields strong therapeutic benefit to tumor-bearing hosts. This work significantly expands our scarce understanding of the pathophysiology and immunobiology of a fundamentally important molecule and has strong implications for the development of novel immunotherapy to treat highly aggressive breast cancers that resist conventional treatment.

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“…ATF3 may play different roles in various tumors. Li et al [ 28 ] found that ATF3 was reduced in esophageal squamous cell carcinoma (ESCC) compared with non-tumor adjacent tissues and ATF3 suppressed ESCC via downregulation of ID1. In bladder cancer, ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression

Chen

Liu

et al. 2018

J Exp Clin Cancer Res

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BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC.MethodsATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3.ResultsThe results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other.ConclusionsOur findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0919-8) contains supplementary material, which is available to authorized users.

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ATF3 suppresses ESCC via downregulation of ID1

Cited by 14 publications

References 42 publications

IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

IFI6 is an effective therapeutic target in esophageal squamous cell carcinoma via the modulation of oxidative stress

Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response

ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression

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