Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome

Denard, Bray; Pavía-Jiménez, Andrea; Chen, Weina; Williams, Noelle S.; Naina, Harris V.; Collins, Robert H.; Brugarolas, James; Ye, Jin

doi:10.1371/journal.pone.0129233

Cited by 20 publications

(19 citation statements)

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“…As doxorubicin was only effective in blocking cell proliferation in CREB3L1-expressing cells, this suggests that only patients expressing CREB3L1 are likely to benefit from doxorubicin treatment. In support of this idea, a recent report showed that higher levels of CREB3L1 expression strongly inversely correlated with tumor volume upon doxorubicin treatment in renal cell carcinoma xenografts ( r = −0.891; p = 0.017) [ 22 ], leading to the suggestion that CREB3L1 could be a biomarker that predicts doxorubicin treatment outcome. These results also suggest that the loss of CREB3L1 may contribute to doxorubicin treatment resistance.…”

Section: Discussionmentioning

confidence: 94%

“…Epigenetic downregulation of CREB3L1 mRNA expression by DNA methylation is associated with increased tumor grade and aggressive phenotype in bladder cancer [ 20 ]. Also, CREB3L1 has been shown to be necessary for the chemotherapeutic drug doxorubicin to block cell proliferation and may function as a biomarker in predicting response to therapy [ 21 , 22 ]. Doxorubicin increases ceramide production, which in turn stimulates regulated intramembrane proteolysis of CREB3L1 to its mature active form.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

et al. 2016

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BackgroundCREB3L1 (cAMP-responsive element-binding protein 3-like protein 1), a member of the unfolded protein response, has recently been identified as a metastasis suppressor in both breast and bladder cancer.MethodsQuantitative real time PCR (qPCR) and immunoblotting were used to determine the impact of histone deacetylation and DNA methylation inhibitors on CREB3L1 expression in breast cancer cell lines. Breast cancer cell lines and tumor samples were analyzed similarly, and CREB3L1 gene methylation was determined using sodium bisulfite conversion and DNA sequencing. Immunohistochemistry was used to determine nuclear versus cytoplasmic CREB3L1 protein. Large breast cancer database analyses were carried out to examine relationships between CREB3L1 gene methylation and mRNA expression in addition to CREB3L1 mRNA expression and prognosis.ResultsThis study demonstrates that the low CREB3L1 expression previously seen in highly metastatic breast cancer cell lines is caused in part by epigenetic silencing. Treatment of several highly metastatic breast cancer cell lines that had low CREB3L1 expression with DNA methyltransferase and histone deacetylase inhibitors induced expression of CREB3L1, both mRNA and protein. In human breast tumors, CREB3L1 mRNA expression was upregulated in low and medium-grade tumors, most frequently of the luminal and HER2 amplified subtypes. In contrast, CREB3L1 expression was repressed in high-grade tumors, and its loss was most frequently associated with triple negative breast cancers (TNBCs). Importantly, bioinformatics analyses of tumor databases support these findings, with methylation of the CREB3L1 gene associated with TNBCs, and strongly negatively correlated with CREB3L1 mRNA expression. Decreased CREB3L1 mRNA expression was associated with increased tumor grade and reduced progression-free survival. An immunohistochemistry analysis revealed that low-grade breast tumors frequently had nuclear CREB3L1 protein, in contrast to the high-grade breast tumors in which CREB3L1 was cytoplasmic, suggesting that differential localization may also regulate CREB3L1 effectiveness in metastasis suppression.ConclusionsOur data further strengthens the role for CREB3L1 as a metastasis suppressor in breast cancer and demonstrates that epigenetic silencing is a major regulator of the loss of CREB3L1 expression. We also highlight that CREB3L1 expression is frequently altered in many cancer types suggesting that it could have a broader role in cancer progression and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0672-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

et al. 2016

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“…The identification of Nr4a1 as a transcription factor of the Creb3l1 gene may have importance in cancer research. The expression levels of Nr4a1 and Creb3l1 have been used a biomarkers to grade cancerous cells/tumors (Alexopoulou et al, 2010 ; Rose et al, 2014 ; Safe et al, 2014 ; Denard et al, 2015 ; Ward et al, 2016 ). No connection has currently been made between Nr4a1 and Creb3l1 expression in cancer cells, but there are studies that support this concept.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1

Greenwood

Gillard

et al. 2017

Front. Mol. Neurosci.

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Cyclic AMP (cAMP) inducible transcription factor cAMP responsive element binding protein 3 like 1 (Creb3l1) is strongly activated in the hypothalamus in response to hyperosmotic cues such as dehydration (DH). We have recently shown that Creb3l1 expression is upregulated by cAMP pathways in vitro, however the exact mechanisms are not known. Here we show that increasing Creb3l1 transcription by raising cAMP levels in mouse pituitary AtT20 cells automatically initiates cleavage of Creb3l1, leading to a greater abundance of the transcriptionally active N-terminal portion. Inhibiting protein synthesis indicated that de novo protein synthesis of an intermediary transcription factor was required for Creb3l1 induction. Strategic mining of our microarray data from dehydrated rodent hypothalamus revealed four candidates, reduced to two by analysis of acute hyperosmotic-induced transcriptional activation profiles in the hypothalamus, and one, orphan nuclear receptor Nr4a1, by direct shRNA mediated silencing in AtT20 cells. We show that activation of Creb3l1 transcription by Nr4a1 involves interaction with a single NBRE site in the promoter region. The ability to activate Creb3l1 transcription by this pathway in vitro is dictated by the level of methylation of a CpG island within the proximal promoter/5′UTR of this gene. We thus identify a novel cAMP-Nr4a1-Creb3l1 transcriptional pathway in AtT20 cells and also, our evidence would suggest, in the hypothalamus.

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“…CREB3L1 is a transcription factor that regulates the expression of many genes, including ER chaperones such as GRP78 42 . Several pieces of evidence have demonstrated the loss of CREB3L1 expression in malignant cancer cells and that the maintenance of CREB3L1 expression could potentially suppress tumorigenesis 16 42 . The bioinformatics analysis and luciferase assays showed that CREB3L1 is a bonafide target of miR-146a during HUVEC angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…CREB3L1 (cAMP responsive element-binding protein 3-like 1; also known as OASIS) is a member of the CREB3b ZIP transcription factor subfamily and was first identified in long-term cultured astrocytes and gliotic tissue 13 . CREB3L1 functions as a transcription factor that regulates target genes with important functions in many physiological processes 14 15 16 . Interestingly, CREB3L1 is down regulated in bladder cancer and acts as a tumor suppressor by directly suppressing tumor cell migration and colony formation 17 .…”

mentioning

confidence: 99%

Up-regulation of FGFBP1 signaling contributes to miR-146a-induced angiogenesis in human umbilical vein endothelial cells

Zhu

Bai

Liu

et al. 2016

Sci Rep

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Recent microRNA expression profiling studies have documented an up-regulation of miR-146a in several angiogenesis models. However, the underlying molecular mechanism of miR-146a in the angiogenic activity of endothelial cells has not been clearly elucidated. The present study was aimed to evaluate whether miR-146a promotes angiogenesis in HUVECs by increasing FGFBP1 expression via directly targeting CREB3L1. miR-146a was over expressed in HUVECs via lentiviral-miR-146a. Expression profiling analysis found miR-146a over expression resulted in up-regulation of angiogenesis and cytokine activity associated genes including FGF2. Further a combination of bioinformatics and experimental analyses demonstrated the CREB3L1 as a bona fide functional target of miR-146a during angiogenesis. Moreover, CREB3L1 inhibited luciferase expression from FGFBP1 promoter containing only CRE elements. Furthermore, CREB3L1 inhibited FGFBP1 expression by binding to two CRE-like sites located at approximately −1780–1777 and −868–865 bp relative to the FGFBP1 transcription start site. Additionally, ectopic expression of CREB3L1 decreased miR-146a-induced FGF2 secretion. These findings indicate that the miR-146a-CREB3L1-FGFBP1 signaling axis plays an important role in the regulation of angiogenesis in HUVECs and provides a potential therapeutic target for anti-angiogenic therapeutics.

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Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome

Cited by 20 publications

References 20 publications

Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers

Regulation of cAMP Responsive Element Binding Protein 3-Like 1 (Creb3l1) Expression by Orphan Nuclear Receptor Nr4a1

Up-regulation of FGFBP1 signaling contributes to miR-146a-induced angiogenesis in human umbilical vein endothelial cells

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