Understanding the regulation of β-catenin expression and activity in colorectal cancer carcinogenesis: beyond destruction complex.

Aberrant Wnt/β-catenin signaling is central to colorectal cancer carcinogenesis. The well-known potential of targeting the canonical Wnt signaling pathway for the treatment of CRC is largely attributed to the ability of this pathway to regulate various cellular processes such as cell proliferation, metastasis, drug resistance, immune response, apoptosis, and cellular metabolism. However, with the current approach of targeting this pathway, none of the Wnt-targeted agents have been successfully implicated in clinical practice. Instead of using classical approaches to target this pathway, there is a growing need to find new and modified approaches to achieve the same. For this, a better understanding of the regulation of β-catenin, a major effector of the canonical Wnt pathway is a must. The present review addresses the importance of understanding the regulation of β-catenin beyond the destruction complex. Few recently discovered β-catenin regulators such as ZNF281, TTPAL, AGR2, ARHGAP25, TREM2, and TIPE1 showed significant potential in regulating the development of CRC through modulation of the Wnt/β-catenin signaling pathway in both in vitro and in vivo studies. Although the expression and activity of β-catenin is influenced by many protein regulators, the abovementioned proteins not only influence its expression and activation but are also directly involved in the development of CRC and various other solid tumors. Therefore, we hypothesise that focusing the current research on finding the detailed mechanism of action of these regulators may assist in providing with a better treatment approach or improve the current therapeutic regimens.