Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer

Asaduzzaman, Muhammad; Constantinou, Stephanie; Min, Haoxiang; Gallon, John; Lin, Mo‐Jun; Singh, Poonam; Raguz, Selina; Ali, Simak; Shousha, Sami; Coombes, R. Charles; Lam, Eric W.‐F.; Hu, Yunhui; Yagüe, Ernesto

doi:10.1007/s10549-017-4202-z

Cited by 77 publications

(68 citation statements)

References 53 publications

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“…Some studies showed that these transcriptional coactivators functioned as tumor-suppressors [9-11], whereas some other studies demonstrated that they were essential for the actions of many oncogenes such as AP-1, c-jun and c-fos [12-14]. Whether CBP promotes apoptosis or cell proliferation appears to be context-dependent, and our study showed here that CBP expression was negatively correlated with the overall survival in lung cancer patients.…”

Section: Introductionsupporting

confidence: 47%

β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells

Zheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: β-catenin is an integral component of the canonical Wnt signaling pathway, and its mutations are an autosomal recessive cause of colorectal cancer (CRC), medulloblastoma (MDB), and ovarian cancer. Nevertheless, little is known about its function in lung cancers. Methods: We first knocked down β-catenin by siRNA to investigate its effects on lung cancer cell proliferation, migration and apoptosis. Then we verified the interaction between β-catenin and CREB binding protein (CBP) by immunofluoresence and co-immunoprecipition assays. Finally, the expression of β-catenin and CBP in human lung adenocarcinoma specimens were analyzed by immunohistochemistry assay. Results: β-catenin knockdown inhibited cell proliferation, promoted apoptosis and suppressed cell migration in A549 and H460 cells accompanied by the decreased expression of Myc, PCNA, VEGF, CD44, MMP-9, MMP-13 and activated bax/caspase-3 pathway. Furthermore, co-immunoprecipition and immunofluoresence analyses revealed that CBP interacted with β-catenin and contributed to β-catenin-mediated lung cancer cell growth. Abolishment of their interaction by the Wnt/β-catenin inhibitor ICG-001 remarkably suppressed cell proliferation. Immunohistochemistry assay of tissue microarrays from patients with lung cancer indicated that both CBP and β-catenin were highly expressed in tumor tissues and predicted poor prognosis in lung adenocarcinoma patients. Conclusions: Our study has provided new evidence for the role of β-catenin in promoting the growth of lung cancer cells through cooperation with CBP, and suggested that dual targeting of β-catenin and CBP could be a potential therapeutic strategy in lung cancer treatment.

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Section: Introductionsupporting

confidence: 47%

β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells

Zheng

et al. 2017

Cell Physiol Biochem

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“…In addition to some well-known tumor suppressors, mutations in epigenetic modifiers have become attractive targets in recent years. Emerging studies have demonstrated that some epigenetic modifiers can function as tumor suppressors in specific malignancies, such as BCOR in T/B lymphocyte malignancies [101][102][103], MLL2 in melanoma and follicular lymphoma [104,105], MLL3 in acute myeloid leukemia [106], ARID1A in gynecological cancers (mammary, ovarian, and uterine cancers) [107][108][109][110], and EP300 in epithelial cancers (colon, breast, and ovarian carcinomas) [111,112]. Mutations in tumor suppressors including some epigenetic modifiers result in the impaired expression of functional proteins, some of which have been shown to be correlated with a poor NKTCL outcome (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Frequent Mutations in Natural Killer/T Cell Lymphoma

Zhang¹,

Li²,

Xue³

et al. 2018

Cell Physiol Biochem

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Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets.

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“…Immunohistochemical staining was performed using antibodies against EP300 (HPA003128, Sigma-Aldrich, St. Louis, MO, USA, dilution 1:200) and E-cadherin (Clone 36, #610181, BD Biosciences, San Jose, CA, USA, dilution 1:200). We have previously validated EP300 antibody specificity using a synthetic peptide, as well as described the standard operating procedure for immunohistochemical staining 15 . All sections were visualized with diaminobenzidine and counterstained with hematoxylin.…”

Section: Ihcmentioning

confidence: 99%

Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

Mahmud

Asaduzzaman

Kumar

et al. 2019

Biochemical Pharmacology

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E-cadherin transcriptional activator EP300 is down-regulated in metaplastic breast carcinoma, a rare form of triple negative and E-cadherin-negative aggressive breast cancer with a poor clinical outcome. In order to shed light on the regulation of Ecadherin by EP300 in breast cancer we analyzed by immunohistochemistry 41 cases of invasive breast cancer with both E-cadherin high and E-cadherin low expression levels, together with 20 non-malignant breast tissues. EP300 and E-cadherin showed a positive correlation in both non-malignant and cancer cases and both markers together were better predictors of lymph node metastasis than E-cadherin alone. These data support a metastasis suppressor role for EP300 in breast cancer. However, some reports suggest an oncogenic role for EP300. We generated a breast cancer cell model to study E-cadherin-independent effects of EP300 by over-expressing of EP300 in HS578T cells which have E-cadherin promoter hypermethylated. In this cell system, EP300 led to up-regulation of mesenchymal (vimentin, Snail, Slug, Zeb1) and stemness (ALDH + and CD44 high /CD24 low ) markers, increases in migration, invasion, anchorage-independent growth and drug resistance. Genome-wide expression profiling identified aldo-keto reductases AKR1C1-3 as effectors of stemness and drug resistance, since their pharmacological inhibition with flufenamic acid restored both doxorubicin and paclitaxel sensitivity and diminished mammosphere formation. Thus, in cells with a permissive E-cadherin promoter, EP300 acts as a tumour / metastasis supressor by up-regulating E-cadherin expression, maintenance of the epithelial phenotype and avoidance of an epithelial-to-mesenchymal transition. In cells in which the E-cadherin promoter is hypermethylated, EP300 functions as an oncogene via upregulation of aldo-keto reductases. This offers the rationale of using current aldo-keto reductase inhibitors in breast cancer treatment.3

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Tumour suppressor EP300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer

Cited by 77 publications

References 53 publications

β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells

β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells

Frequent Mutations in Natural Killer/T Cell Lymphoma

Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

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