Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Stowers Institute for Medical Research, Kansas City, MO, USA.
FEBS Lett. 2019 Oct;593(19):2751-2761. doi: 10.1002/1873-3468.13532. Epub 2019 Jul 21.
Aberrant expression of the glycoprotein mucin-1 (MUC1) has been associated with pancreatic cancer progression and metastasis as a result of mediating the oncogenic transcriptional regulation of target genes. In the present study, we demonstrate that MUC1 downregulates the expression of the tumor suppressor polypeptide N-acetylgalactosaminyltransferase 5 in pancreatic cancer. ChIP-on-chip analysis revealed that the MUC1 cytoplasmic tail binds to regulatory elements in the GALNT5 gene. Additionally, MUC1 increases binding of p53 and c-Jun and decreases the binding of Sp1 to the proximal promoter and exonic regions of GALNT5. We also observed that expression of N-acetylgalactosaminyltransferase 5 is inversionally proportional to MUC1 expression in human pancreatic cancer. These results demonstrate that MUC1 downregulates the expression of N-acetylgalactosaminyltransferase 5 in pancreatic cancer by modifying the promoter occupancy of transcription factors through its cytoplasmic domain.
糖蛋白黏蛋白-1（MUC1）的异常表达与胰腺癌的进展和转移有关，这是由于其介导了靶基因的致癌转录调控。在本研究中，我们证明 MUC1 下调了胰腺癌中肿瘤抑制多肽 N-乙酰半乳糖胺转移酶 5 的表达。ChIP-on-chip 分析显示，MUC1 胞质尾与 GALNT5 基因的调控元件结合。此外，MUC1 增加了 p53 和 c-Jun 的结合，减少了 Sp1 与 GALNT5 近端启动子和外显子区域的结合。我们还观察到，在人胰腺癌中，N-乙酰半乳糖胺转移酶 5 的表达与 MUC1 的表达呈反比关系。这些结果表明，MUC1 通过其胞质结构域改变转录因子的启动子占有率，从而下调胰腺癌中 N-乙酰半乳糖胺转移酶 5 的表达。
