The correlation between the loss of Profilin 1 (Pfn1) with tumor progression indicated that Pfn1 is a tumor suppressor in human carcinoma. The molecular mechanisms underlying Pfn1 tumor suppression has yet to be elucidated. In this study, we showed that Pfn1 overexpression sensitizes cancer cells to apoptosis through the typical intrinsic apoptotic pathway. Mechanistically, the increased Pfn1 expression mediated the upregulation of p53R273H, one of the most common tumor-associated hotspot mutations of p53, with transactivation deletion in tumorigenesis and increased localization of p53R273H in cytoplasm. Further studies showed that mutant p53R273H was involved in apoptosis induced by Staurosporine (STS) via transcription-independent mitochondrial functions. We observed (i) the increased cytosolic localization of p53R273H, (ii) the activation of phosphorylation at Ser15, (iii) its mitochondrial localization; Pfn1 acted as a positive regulator of these processes. We also found that Pfn1 interacted with p53R273H and thus facilitated its exertion over the transcription-independent activity in the cytoplasm during drug action. Our results define a new function and mechanism of Pfn1 demonstrating that the combined effect with apoptotic agents led to a synergistic increase in apoptosis. In addition, p53R273H abrogating DNA binding was found to play a major role in the Pfn1- sensitized apoptosis through a transactivation-independent and cytosolic activity.
Methyl-CpG binding domain protein 1 (MBD1) has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression and development. It is also predicted that MBD1 might be involved in tumor development and progression. However, whether and how MBD1 is involved in tumorigenesis, especially in pancreatic cancer (PC), is currently unknown. We found that MBD1 was significantly up-regulated in PC tissues compared with the surrounding normal tissues according to RT-PCR data. Tissue microarray (TMA) based immunohistochemical study from 58 surgically resected PC specimens indicated that higher MBD1 expression correlated with lymph node metastasis and poor survival in PC patients. Gain- and loss-of-function studies in vitro validated MBD1 as a potent oncogene promoting PC cell invasion as well as epithelial-mesenchymal transition (EMT). Mechanistically, MBD1 is associated with Twist and NAD-dependent deacetylase sirtuin-1 (SIRT1), thereby forming the Twist-MBD1-SIRT1 complex on the CDH1 promoter, which resulted in reduced E-cadherin transcription activity and increased cell EMT ability. Significantly, targeting MBD1 reversed the EMT phenotype of PC and restored sensitivity to chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in PC invasion and metastasis by providing a molecular mechanism underlying MBD1-promoted EMT. Thus MBD1 may serve as a potential therapeutic target for PC.
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