Up-Regulation of MBD1 Promotes Pancreatic Cancer Cell Epithelial-Mesenchymal Transition and Invasion by Epigenetic Down-Regulation of E-Cadherin

Abstract

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.

Hypoxia inducible factor (HIF)-1α directly activates leptin receptor (Ob-R) in pancreatic cancer cells

“…Pancreatic cancer remains one of the deadliest of all cancers, despite aggressive surgical treatment combined with adjuvant radiotherapy and chemotherapy [9][10][11][12][32][33][34][35][36][37]. Gemcitabine remains to be the standard first line therapy for patients with un-resectable pancreatic cancer [32].…”

“…Although FOLFIRINOX has recently been identified as a new regimen for pancreatic cancer (OS 11.1 vs 6.5 of Gemcitabine), the adverse effect is intolerable for many patients [33]. Chemo-resistance and radio-resistance are the principal causes of failure for pancreatic cancer patients to respond to therapy and some studies also suggest that a number of genes or mechanisms are involved in the development of pancreatic cancer [34][35][36][37]. Recombinant methionyl human leptin, an analog of human leptin has been approved by FDA for the treatment of Metabolic Abnormalities associated with Lipodystrophy [1][2][3][4][5][6][7].…”

Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial–mesenchymal transition in cancer cells

“…It has been reported that SIRT1 is overexpressed and facilitates acinar to ductal metaplasia in pancreatic cancer (Xu, Zhu, et al, ; Zhao et al, ) and is a positive regulator of tumorigenesis and metastases (Palmirotta et al, ). Also, Deng et al () showed that the silencing of SIRT1 leads to restoration of the expression of E‐cadherin, while N‐cadherin, Snail, and Zeb1 was downregulated in the BxPC‐3 and PANC‐1 cells which decreased cell motility and migration ability in PANC‐1 cells.…”

“…Furthermore, MMP8 facilitates SIRT1‐Zeb1 interaction through association with Zeb1 (Sun et al, ). Also, according to studies, a transcriptional repressor complex including SIRT1, Twist1, and methyl‐CpG binding domain (MBD) protein‐1, can suppress the expression of E‐cadherin (Alivand, Soheili, Pornour, Solali, & Sabouni, ; Xu, Zhu, et al, ) (Figure ).…”

LyP‐1‐fMWNTs enhanced targeted delivery of MBD1siRNA to pancreatic cancer cells

“…7 More detailed studied also revealed that the MBD1 could affect the invasion, metastasis sensitivity of cells to radiation and chemical therapy in PDAC. 31,32 Our study incorporated the MBD1siRNA plasmid into the carbon nanotube carriers to confirm the therapeutic effect in PDAC. However, the similar MBD1 nanoparticles had no specificity to PDAC cells.…”