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.
Keywords: Drug resistance, EMT, MBD1, PC, SIRT1, Twist
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