Understanding the role of SATB family chromatin organizers in tumorigenesis

SATB family chromatin organizers are known to orchestrate chromatin architecture and regulate global gene expression. Recently, these two chromatin organizers have been shown to dynamically regulate colorectal cancer progression. We showed for the first time that SATB1 shares a feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt signaling-dependent regulation of β-catenin. Our studies provide unequivocal evidence that SATB1 reprograms the expression of tumor growth- and metastasis-associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling critical for colorectal cancer tumorigenesis. In-depth mechanistic understanding of regulation of SATB1 across colorectal cancer, implicated a need to develop anticancer therapy by targeting SATB1. In this context we are studying the role of statins, which we have shown to specifically target SATB1.

Model depicting the proposed molecular mechanism for regulation of SATB1 and its functional consequences. In Wnt-ON state, β-catenin levels increase through stabilization. Subsequent to nuclear accumulation of β-catenin, the TCF7L2/β-catenin complex binds to Satb1 promoter and induces its expression. SATB1/β-catenin complex binds to Tcf7l2 promoter to maintain its expression. The TCF7L2:β-catenin and SATB1:β-catenin complexes subsequently bind to multiple Wnt responsive genes to induce their expression.

Research In Focus

Title: Regulation of transcription factor SP1 by β-catenin destruction complex modulates Wnt response

Authors: Rafeeq Mir, Ankita Sharma, Saurabh J Pradhan, and Sanjeev Galande

Journal Published: Molecular and Cellular Biology

Model depicting the proposed molecular mechanism for regulation of SATB1 and its functional consequences. In Wnt-ON state, β-catenin levels increase through stabilization. Subsequent to nuclear accumulation of β-catenin, the TCF7L2/β-catenin complex binds to Satb1 promoter and induces its expression. SATB1/β-catenin complex binds to Tcf7l2 promoter to maintain its expression. The TCF7L2:β-catenin and SATB1:β-catenin complexes subsequently bind to multiple Wnt responsive genes to induce their expression.

Cancer Biology Research Group

Acknowledgments:  Greg Dsilva and Manu Unni