Human MTA1 blocking peptide

Objectives: So far, there are no investigations about the role of histone deacetylase 1 (HDAC1) in tumorigenesis of pancreatic ductal adenocarcinoma. This study was designed to elucidate the roles and mechanisms of HDAC1 in tumorigenesis of pancreatic ductal adenocarcinoma. Methods: Real-time reverse transcription-polymerase chain reaction and immunohistochemistry techniques were adopted to detect the expression of HDAC1 in human pancreatic ductal adenocarcinoma tissues and paired paracancerous tissues. The roles of HDAC1 in human pancreatic cell line PaTu8988 were investigated using siRNA. Results: Histone deacetylase 1 mRNA in pancreatic cancer tissues were significantly higher than in paracancerous tissues (P < 0.05). Immunohistochemistry showed that the indices of HDAC1 in pancreatic cancer tissues and paracancerous tissues were 56.4% (SD, 23.1%) and 6.7% (SD, 5.0%), respectively (P < 0.001). Knockdown of HDAC1 can generate a remarkable defect in proliferation and also can significantly induce apoptosis and S-phase arrest in PaTu8988 cells (P < 0.05). The Bcl-2 mRNA expression was significantly downregulated, whereas the p21 and Bax mRNA expression were significantly upregulated. Conclusions: The HDAC1 overexpression might play an important role in tumorigenesis of pancreatic cancer. Our data support the development of selective inhibitors targeting HDAC1 for the treatment of pancreatic ductal adenocarcinoma. Histone deacetylase 1 could be a new gene therapy target in pancreatic ductal adenocarcinoma.

LIM domain only 4 (LMO4), a member of the LIM-only family of transcriptional coregulatory proteins, consists of two LIM protein-protein interaction domains that enable it to function as a linker protein in multiprotein complexes. Here, we have identified estrogen receptor alpha (ER alpha) and its corepressor, metastasis tumor antigen 1 (MTA1), as two novel binding partners of LMO4. Interestingly, LMO4 exhibited binding with both ER alpha and MTA1 and existed as a complex with ER alpha, MTA1, and historic deacetylases (HDAC), implying that LMO4 was a component of the MTA1 corepressor complex. Consistent with this notion, LMO4 overexpression repressed ER alpha transactivation functions in an HDAC-dependent manner. Accordingly, silencing of endogenous LMO4 expression resulted in a significant increased recruitment of ER alpha to target gene chromatin, stimulation of ER alpha transactivation activity, and enhanced expression of ER alpha-regulated genes. These findings suggested that LMO4 was an integral part of the molecular machinery involved in the negative regulation of ER alpha transactivation function in breast cells. Because LMO4 is up-regulated in human breast cancers, repression of ER alpha transactivation functions by LMO4 might contribute to the process of breast cancer progression by allowing the development of ER alpha-negative phenotypes, leading to increased aggressiveness of breast cancer cells.