Regulation of High Mobility Group A1 expression by the Adenomatous polyposis coli (Apc) tumor suppressor gene

Abstract

High Mobility Group A1 (HMGA1) is disregulated in neoplasias and is a prominent biomarker for colon cancer. However, the molecular networks involved in HMGA1‐mediated transformation are only partially understood. Mutations in the adenomatus polyposis coli (Apc) gene are associated with the earliest stages of colon carcinogenesis. These mutations activate the Wnt signaling pathway, resulting in stabilization of beta‐catenin which then binds to T‐cell factor‐4 (Tcf‐4) causing subsequent increases in target gene expression. We explored the role of the Wnt pathway in HMGA1 regulation. In Apc(Min/ +) mice expressing truncated Apc, we observed 9‐fold greater HMGA1 mRNA levels relative to mice bearing wild‐type Apc. HMGA1 protein levels were also significantly elevated in Apc (Min/+) intestinal tumors. To assess the effects of wild type Apc recovery, we used HT‐29 cells (human colorectal carcinoma cell line with truncated Apc) in which wild type Apc has been introduced under the control of a zinc inducible promoter. Induction of full length Apc caused down‐regulation of HMGA1 at the translational level suggesting a novel role for HMGA1 in Wnt signaling. Current studies are aimed at understanding the mechanism by which HMGA1 expression is regulated using MALDI‐TOF mass spectrometry. Our data implicates Wnt signal transduction as a regulator of HMGA1 in colon cancer. Work funded by NIH P20RR16461, NSF 0542242; 0722722.