APEX-1 up-regulates Jagged/Notch activity to promote colon cancer

▸ Kim MH, Kim HB, Yoon SP, et al. Colon cancer progression is driven by APEX1-mediated upregulation of Jagged. J Clin Invest Published Online First: 21 July 2013. doi:10.1172/JCI65521

Apurinic-apyrimidinic endonuclease-1 (APEX1) is a protein that stimulates the DNA-binding activity of several transcriptional factors involved in cancer promotion and progression. Atypical expression and sub-cellular localisation of APEX1 have been related to clinical stage and poor prognosis in various solid tumors; however, its exact role in tumourigenicity remains to be elucidated. In this study, Kim and colleagues investigate the role of APEX1 in colon cancer progression. Tumourigenic effects of APEX1 were evaluated in a noncancerous, immortalised human fibroblast cell line, as well as colon cancer cell lines. APEX1 knockdown resulted in reduced cell proliferation and tumourigenic features in the cell lines, while over expression promoted cancer progression. The effects of APEX1 on tumour formation and progression were tested in vivo using mouse xenograft models. After injection of APEX1-knockdown colon cancer cells into nude mice, pulmonary tumour growth and metastasis were decreased compared with controls. Conversely, there was increased tumour growth and metastasis when APEX1-overexpressed cells were injected into the mice. Using cDNA microarrays, JAG1, which encodes the major Notch ligand Jagged1, was identified as a direct transcriptional target of APEX1. Jagged1 is up regulated in a number of cancers, including prostate, breast, ovarian, and colorectal. The APEX1 mediated increase in Jagged1 transcription resulted from increased binding of the transcription factor EGR1 to the Jagged1 promoter. EGR1 knockdown caused down regulation of Jagged1 in colon cancer cells that strongly expressed APEX1. Demonstrating clinical relevance, the authors identified strong expression of APEX1 and Jagged1 in human colon carcinoma tissues, while these proteins were expressed at low levels in normal colon tissues. Taken together, this study demonstrates that APEX1 positively regulates Notch signalling …