SMAR1 inhibits Wnt/ β-catenin signaling and prevents colorectal cancer progression.

SMAR1 inhibits Wnt/β-catenin signaling and prevents colorectal cancer progression. Oncotarget. 2018 Apr 20;9(30):21322-21336 Authors: Taye N, Alam A, Ghorai S, Chatterji DG, Parulekar A, Mogare D, Singh S, Sengupta P, Chatterjee S, Bhat MK, Santra MK, Salunkhe PB, Finston SK, Chattopadhyay S Abstract Reduced expression of Scaffold/Matrix Attachment Region Binding Protein 1 (SMAR1) is associated with various cancers resulting in poor prognosis of the diseases. However, the precise underlying mechanism elucidating the loss of SMAR1 requires ongoing study. Here, we show that SMAR1 is highly downregulated during aberrant Wnt3a signaling due to proteasomal degradation and predicted poor prognosis of colorectal cancer. However, substitution mutation (Arginine and Lysine to Alanine) in the D-box elements of SMAR1 viz. "RCHL" and "RQRL" completely abrogated its proteasomal degradation despite Wnt3a activity. SMAR1 inhibited Wnt/β-catenin signaling by recruiting Histone deacetylase-5 to β-catenin promoter resulting in reduced cell migration and invasion. Consequently, reduced tumor sizes in in-vivo NOD-SCID mice were observed that strongly associated with suppression of β-catenin. However, loss of SMAR1 led to enriched H3K9 Acetylation in the β-catenin promoter that further increased Wnt/β-catenin signaling activities and enhanced colorectal cancer progression drastically. Using docking and isothermal titration calorimetric studies we s...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research