Chromatin immunoprecipitation assays showed that Doxorubicin induced DNA damage Cinoxacin consequently leads to the recruitment of acetylated p53 on SMAR1 promoter and thus activate its transcription. Along with p53 acetylation, recruitment of p53 dependent activator complex on SMAR1 promoter also resulted in H3-K9 acetylation indicative of active chromatin at the locus. Once SMAR1 reaches a threshold expression, it allows deacetylation of p53 as shown upon SMAR1 overexpression. Upregulation of acetylated p53 is followed by induction in SMAR1 expression that is further correlated with the cell cycle where the SMAR1 expression was highest during G1/S phase. Prolonged treatment of Doxorubicin resulted in G2/M arrest, which can be explained due to SMAR1 mediated stabilization of p53 in the nucleus. siRNA treatment of SMAR1 inhibited Doxorubicin mediated cell cycle arrest. Cell cycle progression is thus regulated by p53 in response to DNA damage through regulation of SMAR1 expression that is directly involved in chromatin remodeling at the Cyclin D1 promoter loci. This suggests that SMAR1 functions in Atractylenolide-III synergism with the Doxorubicin by conferring selective repressor activity to p53 through its deacetylation that results only in cell cycle arrest and not apoptosis. Thus, in addition to previously reported pathways here we report a new positive feedback regulation between p53 and SMAR1 where SMAR1 is transcriptionally activated by p53 and that in turn stabilize p53 by facilitating phosphorylation at serine 15 residue. The expression of SMAR1 is drastically downregulated during breast cancer progression and is inversely correlated with Cyclin D1 expression. Interestingly, we observed that acetylated p53 at K373/382 showed diffused expression in the nuclear spaces with higher expression in the nucleolar compartments in breast fibroadenoma 
and exclusively nucleolar translocation in IDC G-III samples. These observations suggest that mutations in p53 may lead to its altered status and expression pattern in human breast carcinoma and is associated with its sequestration into heterochromatin resulting in its compromised activity. Similar correlation between p53 localization was observed in various breast carcinoma cell lines where p53 and acetylated p53 were predominantly present in the heterochromatin regions. All above observations suggest a possible mechanism of SMAR1 dysregulation in breast cancer due to abnormal p53 acetylation, phosphorylation and its sub-cellular sequestration. Moreover, SMAR1 leads to reduced migration and invasion in both poorly and highly metastatic breast carcinoma cell lines irrespective of p53 status in both transient and stably SMAR1 transfected cells through downregulation of TGFb signaling and its target gene expression including CUTL1. Earlier we have reported that SMAR1 inhibits ERK phosphorylation that may contribute to decreased phospho-Smad2 levels and thus inhibits TGFb signaling. SMAR1 is also able to reduce metastatic potential of B16F1 cells in-vivo in mice model. Microarray analysis done in SMAR1 stable clone, showing downregulation of various oncogenes, Cyclins, focal-adhesion molecules, TGFb related genes and upregulation of various growth inhibitory, DNA repair and stress response genes also indicated anti-tumorigenic and antimetastatic function of SMAR1. Our results establish SMAR1, as a critical regulator of TGFb signaling cascade that finally affect CUTL1 expression. Downregulation of SMAR1 in high-grade breast carcinoma can be directly correlated with activated TGFb signaling and its downstream target genes that consequently lead to increased tumor metastasis.