Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy

Wu, Xingda; Liu, Ning; Li, Xiaoying; Meng, Fanchao; Song, Shuai

doi:10.1002/cbin.10760

Cited by 14 publications

(14 citation statements)

References 27 publications

(58 reference statements)

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“…ATF2 is known to regulate the expression of its target genes, including those involving apoptosis, cell proliferation and DNA damage response ( 6 , 16 ). Accordingly, ATF2 activation has been correlated with the growth of some neoplasms, such as spindle cell carcinoma of the skin ( 17 ), extramammary Paget’s disease ( 18 ), head and neck squamous cell carcinoma ( 19 ), synovial sarcoma ( 20 ) and pancreatic cancer ( 21 ). Interestingly, loss of ATF2 function has also been observed in other malignancies, such as breast and lung carcinomas as well as neuroblastoma ( 22 ), implying that the balance of tissue-specific compositions of ATF2-AP1 dimers is critical for transcriptional programs for cell survival vs cell death ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several immunohistochemical studies have determined the expression levels of ATF2, p-ATF2 and/or p-ERK in human tumor specimens. In particular, ATF2 and/or p-ATF2 were found to be significantly elevated in pancreatic cancer ( 21 ), prostate cancer ( 29 ) and spindle cell carcinoma of the skin ( 17 ), compared with respective normal/benign controls. In addition, ATF2 or p-ATF2 overexpression in breast cancer tissues was shown to associate with lower disease-free survival ( P = 0.079) or higher overall survival ( P = 0.047) rates, respectively ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

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ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

Inoue

Mizushima

Ide

et al. 2018

Endocrine Connections

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We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

Inoue

Mizushima

Ide

et al. 2018

Endocrine Connections

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Section: Introductionmentioning

confidence: 99%

“…Apart from melanoma, ATF2 was also investigated in pancreatic cancer revealing an upregulation of ATF2 in cancer tissues compared to adjacent non-tumour material (113). Silencing of ATF2 resulted in inhibition of proliferation, induction of apoptosis and rendered tumour cells susceptible to the anti-tumour drug gemcitabine (113). The oncogenic duality of ATF2 was further studied in bladder cancer where ATF2 activation was shown to be dependent on the androgen receptor (AR) with ATF2 activity being positively correlated to AR-induced urothelial tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

The activating transcription factor 2: an influencer of cancer progression

Huebner

Procházka

et al. 2019

Mutagenesis

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In contrast to the continuous increase in survival rates for many cancer entities, colorectal cancer (CRC) and pancreatic cancer are predicted to be ranked among the top 3 cancer-related deaths in the European Union by 2025. Especially, fighting metastasis still constitutes an obstacle to be overcome in CRC and pancreatic cancer. As described by Fearon and Vogelstein, the development of CRC is based on sequential mutations leading to the activation of proto-oncogenes and the inactivation of tumour suppressor genes. In pancreatic cancer, genetic alterations also attribute to tumour development and progression. Recent findings have identified new potentially important transcription factors in CRC, among those the activating transcription factor 2 (ATF2). ATF2 is a basic leucine zipper protein and is involved in physiological and developmental processes, as well as in tumorigenesis. The mutation burden of ATF2 in CRC and pancreatic cancer is rather negligible; however, previous studies in other tumours indicated that ATF2 expression level and subcellular localisation impact tumour progression and patient prognosis. In a tissue- and stimulus-dependent manner, ATF2 is activated by upstream kinases, dimerises and induces target gene expression. Dependent on its dimerisation partner, ATF2 homodimers or heterodimers bind to cAMP-response elements or activator protein 1 consensus motifs. Pioneering work has been performed in melanoma in which the dual role of ATF2 is best understood. Even though there is increasing interest in ATF2 recently, only little is known about its involvement in CRC and pancreatic cancer. In this review, we summarise the current understanding of the underestimated ‘cancer gene chameleon’ ATF2 in apoptosis, epithelial-to-mesenchymal transition and microRNA regulation and highlight its functions in CRC and pancreatic cancer. We further provide a novel ATF2 3D structure with key phosphorylation sites and an updated overview of all so-far available mouse models to study ATF2 in vivo.

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“…Previous studies have reported that ATF2 is involved in the pathobiology of numerous cancers. For example, ATF2 exhibits oncogenic functions in prostate cancer [7], melanoma [6,8], renal cell carcinoma [9] and pancreatic cancer [10]. Conversely, ATF2 exerts a tumor suppressor role in breast cancer [11] and skin cancer [12], suggesting a tumor-specific characteristic of ATF2 function.…”

Section: Introductionmentioning

confidence: 99%

The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression

Liu

Wang

et al. 2020

Cancer Cell Int

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Background Activating transcription factor 2 (ATF2), a member of the activator protein 1 (AP-1) transcription factor family, has been shown to be involved in the pathobiology of numerous cancers. However, the biological role and mechanism of ATF2 in lung adenocarcinoma (LUAD) remains to be elucidated. Methods The expression of ATF2, NEAT1 and miR-26a-5p in LUAD tissues and cell lines was detected by qRT-PCR and western blotting. The interaction between ATF2, NEAT1, and miR-26a-5p was validated by chromatin immunoprecipitation, luciferase reporter assay and RNA immunoprecipitation. Cell proliferation, invasion and tumorigenesis of LUAD cells were analyzed by using CCK8, transwell invasion assay and xenograft tumor model. Results We confirmed that ATF2 expression was increased in LUAD tissues compared with normal adjacent lung tissues. Functional experiments showed that ATF2 positively regulated cell proliferation and invasion in LUAD cells. Moreover, we identified that NEAT1 expression was increased in LUAD tissues and positively correlated with ATF2 expression. Mechanistically, ATF2 could bind to the promoter of NEAT1 to promote its transcription. Rescue experiments showed that ATF2 exerted its oncogenic function in LUAD, at least, partly through NEAT1 upregulation. In turn, NEAT1 could positively regulate ATF2 expression and form a positive feedback loop in LUAD cells. Furthermore, we demonstrated that NEAT1 positively regulated ATF2 expression via sponging miR-26a-5p. Conclusion ATF2 and NEAT1 form a positive feedback loop mediated by miR-26a-5p and coordinately contribute to LUAD progression.

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Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy

Cited by 14 publications

References 27 publications

ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

The activating transcription factor 2: an influencer of cancer progression

The interplay between ATF2 and NEAT1 contributes to lung adenocarcinoma progression

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