p53 target gene SMAR1 is dysregulated in breast cancer: its role in cancer cell migration and invasion

• Published in: PloS one 2007-08, Vol.2 (7), p.e660-e660
• Main Authors: Singh, Kamini, Mogare, Devraj, Giridharagopalan, Ramprasad Obula, Gogiraju, Rajinikanth, Pande, Gopal, Chattopadhyay, Samit
• Format: Article
• Language: English
• Subjects: Acetylation; Anthracyclines; Apoptosis; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer genetics; Cancer metastasis; Cell adhesion & migration; Cell Biology/Cell Adhesion; Cell Biology/Cell Growth and Division; Cell Biology/Cell Signaling; Cell Biology/Gene Expression; Cell cycle; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell migration; Cell Movement - genetics; Cell Nucleus - metabolism; Cell Nucleus - pathology; Correlation; Cyclin D1; Cytoplasm - metabolism; Cytoplasm - pathology; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - genetics; Doxorubicin; Extracellular matrix; Female; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Growth factors; Heterochromatin; Humans; Kinases; Leukocyte migration; Metastases; Metastasis; Molecular biology; Neoplasm Invasiveness - genetics; Neoplasm Metastasis - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Staging; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology/Breast Cancer; p53 Protein; Phosphorylation; Polymerization; Protein Processing, Post-Translational; Proteins; Recruitment; Rodents; Serine; Transcription (Genetics); Transcription activation; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming growth factors; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000660

Tumor suppressor SMAR1 interacts and stabilizes p53 through phosphorylation at its serine-15 residue. We show that SMAR1 transcription is regulated by p53 through its response element present in the SMAR1 promoter. Upon Doxorubicin induced DNA damage, acetylated p53 is recruited on SMAR1 promoter that allows activation of its transcription. Once SMAR1 is induced, cell cycle arrest is observed that is correlated to increased phospho-ser-15-p53 and decreased p53 acetylation. Further we demonstrate that SMAR1 expression is drastically reduced during advancement of human breast cancer. This was correlated with defective p53 expression in breast cancer where acetylated p53 is sequestered into the heterochromatin region and become inaccessible to activate SMAR1 promoter. In a recent report we have shown that SMAR1 represses Cyclin D1 transcription through recruitment of HDAC1 dependent repressor complex at the MAR site of Cyclin D1 promoter. Here we show that downmodulation of SMAR1 in high grade breast carcinoma is correlated with upregulated Cyclin D1 expression. We also established that SMAR1 inhibits tumor cell migration and metastases through inhibition of TGFbeta signaling and its downstream target genes including cutl1 and various focal adhesion molecules. Thus, we report that SMAR1 plays a central role in coordinating p53 and TGFbeta pathways in human breast cancer.