CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion

Sasaki, Yasushi; Koyama, Ryota; Maruyama, Reo; Hirano, Takehiro; Tamura, Miyuki; Sugisaka, Jun; Suzuki, Hiromu; Idogawa, Masashi; Shinomura, Yasuhisa; Tokino, Takashi

doi:10.4161/cbt.22280

Cited by 56 publications

(55 citation statements)

References 36 publications

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“…Interestingly, reduced expression of CLCA2 was frequently observed in breast cancer (26). In addition, CLCA2 was shown to play a crucial role in inhibition of cancer cell migration and invasion (27,28). We confirmed by qPCR that CLCA2 expression was substantially elevated after Fra-1 or c-Jun depletion (Fig.…”

Section: Fra-1 and C-jun Common Target Genes Regulating Cell Prolifersupporting

confidence: 71%

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

et al. 2014

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Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties. Cancer Res; 74(14); 3983-94. Ó2014 AACR.

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Section: Fra-1 and C-jun Common Target Genes Regulating Cell Prolifersupporting

confidence: 71%

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

et al. 2014

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“…So far, the most important reported inductor is TP53. 15,16,21 On the other hand, epigenetic regulation came out as a key factor that represses CLCA2 expression in malignant tissues, 13,15 but how this is regulated is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR‐196b‐5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease

Porretti

Dalton

Massillo

et al. 2018

Intl Journal of Cancer

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Prostate cancer (PCa) is the most common cancer among men. Metabolic syndrome (MeS) is associated with increased PCa aggressiveness and recurrence. Previously, we proposed C-terminal binding protein 1 (CTBP1), a transcriptional co-repressor, as a molecular link between these two conditions. Notably, CTBP1 depletion decreased PCa growth in MeS mice. The aim of this study was to investigate the molecular mechanisms that explain the link between MeS and PCa mediated by CTBP1. We found that CTBP1 repressed chloride channel accessory 2 (CLCA2) expression in prostate xenografts developed in MeS animals. CTBP1 bound to CLCA2 promoter and repressed its transcription and promoter activity in PCa cell lines. Furthermore, we found that CTBP1 formed a repressor complex with ZEB1, EP300 and HDACs that modulates the CLCA2 promoter activity. CLCA2 promoted PCa cell adhesion inhibiting epithelial-mesenchymal transition (EMT) and activating CTNNB1 together with epithelial marker (CDH1) induction, and mesenchymal markers (SNAI2 and TWIST1) repression. Moreover, CLCA2 depletion in PCa cells injected subcutaneously in MeS mice increased the circulating tumor cells foci compared to control. A microRNA (miRNA) expression microarray from PCa xenografts developed in MeS mice, showed 21 miRNAs modulated by CTBP1 involved in angiogenesis, extracellular matrix organization, focal adhesion and adherents junctions, among others. We found that miR-196b-5p directly targets CLCA2 by cloning CLCA2 3'UTR and performing reporter assays. Altogether, we identified a new molecular mechanism to explain PCa and MeS link based on CLCA2 repression by CTBP1 and miR-196b-5p molecules that might act as key factors in the progression onset of this disease.

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“…Our previous microarray study identified several downstream target genes of p53 family proteins (Affymetrix GeneChip, Santa Clara, CA, USA) (NCBI Gene Expression Omnibus database, accession number GSE 13504; https:// www.ncbi.nlm.nih.gov/geo/). (10,11) In the current study, we validated some of these upregulated genes by real-time RT-PCR and immunoblot analyses. One such gene is BRMS1L, a component of the mSin3/histone deacetylase 1 (HDAC1) repressive machinery.…”

Section: Resultsmentioning

confidence: 91%

Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53

et al. 2017

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The tumor suppressor p53 and its family members, p63 and p73, play a pivotal role in the cell fate determination in response to diverse upstream signals. As transcription factors, p53 family proteins regulate a number of genes that are involved in cell cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 family proteins are important for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis suppressor 1‐like (BRMS1L) is upregulated by p53 family proteins, specifically p53, TAp63γ, and TAp73β. We identified two responsive elements of p53 family proteins in the first intron and upstream of BRMS1L. These response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effect. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Together, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and that it inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results indicate that BRMS1L is involved in cancer cell invasion and migration, and could be a therapeutic target for cancer.

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CLCA2, a target of the p53 family, negatively regulates cancer cell migration and invasion

Cited by 56 publications

References 36 publications

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer

CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR‐196b‐5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease

Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53

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