Statin mediated regulation of SATB family of proteins and β-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/β-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/β-catenin signaling, specifically targeting the chromatin organizer SATB1 and β-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 β-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 β-catenin interactome in statin treated cells revealed multiple novel partners including Farnesyl pyrophosphate synthase, an enzyme crucial for farnesylation of target proteins. The in silico analysis to assess the possibility of a farnesyl modification on β-catenin confirmed occurrence of the consensus motif ‘CAAX’. We delineated Cysteine 419 as a novel farnesyl modified residue in β-catenin, mutation of which resulted in the loss of nuclear localization of β-catenin. Furthermore, we observed that statin treatment reduces the farnesylation modification as well. However, removal of the farnesyl modification is not enough for the statin mediated degradation of β-catenin. We found that another stabilization factor, PCAF, was also downregulated on statin treatment. Furthermore, the interaction between PCAF and β-catenin was lost upon statin treatment, suggesting a dual mechanism by which β-catenin is destabilized and degraded. Collectively, these results underscore the molecular mechanism of antitumor activity of statins, targeting the upstream players in a crucial tumorigenic pathway, potentially providing new therapeutic possibilities.