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

Oncotarget
Nandaraj TayeSamit Chattopadhyay

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 show that small microbial peptides viz. AT-01C and AT-01D derived from Mycobacterium tuberculosis m...Continue Reading

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Citations

Jan 11, 2020·Frontiers in Immunology·Sonal PatelSamit Chattopadhyay
Apr 18, 2021·Cancer & Metabolism·Arpankumar ChoksiSamit Chattopadhyay
Aug 28, 2021·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Richa PantSamit Chattopadhyay

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Methods Mentioned

BETA
PCR
transfection
immunoprecipitation
ChIP-PCR
flow cytometry
ChIP
Acetylation
Isothermal Titration Calorimetry
restriction
X-ray

Software Mentioned

SigmaPlot
CellQuest Pro
AutoDock
Wiz
MAR

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