Statin mediated regulation of satb family of proteins and 206 178 catenin in colorectal cancer

Abstract

Colorectal cancer (CRC) is the second highest cause for cancer-driven mortality worldwide, justifying the continued extensive research to delineate the tumorigenic mechanisms and new therapeutic regimes. The aberrant activation of Wnt/and#946;-catenin signaling is one of the major mechanisms responsible for adenoma formation. However, current therapies do not entail targeting this pathway directly. Statins are family of drugs that target the mevalonate pathway leading to reduction in serum cholesterol levels. Here, we provided evidence of anti-tumor activity of statins in vitro and in vivo using a multi-pronged approach. Through the integrative analysis of transcriptomics, proteomics and lipidomics data, we demonstrated that statins downregulate tumor promoting pathways including Wnt/and#946;-catenin signaling, specifically targeting the chromatin organizer SATB1 and and#946;-catenin for degradation. We further showed that statins alter the expression profile of SATB family of proteins by downregulating SATB1 and upregulating SATB2. Analysis of biopsy specimens from CRC patients using immunoblot and immunohistochemistry further suggested differential expression of SATB proteins as key in determining the tumorigenic outcome. Mechanistically, we observed degradation of and#946;-catenin upon statin treatment via a link between the cholesterol pathway and Wnt signaling. Strikingly, this degradation seemed to be phosphorylation-independent and occured specifically via the lysosomal route. Analysis of and#946;-catenin interactome in statin treated cells revealed multiple novel partners including Farnesyl pyrophosphate synthase, an enzyme crucial for farnesylation of target proteins. newline