Oncotarget

Research Papers:

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

Nandaraj Taye, Aftab Alam, Suvankar Ghorai, Deya Ghosh Chatterji, Apoorva Parulekar, Devraj Mogare, Snahlata Singh, Pallabi Sengupta, Subhrangsu Chatterjee, Manoj Kumar Bhat, Manas Kumar Santra, Prabhakar Budha Salunkhe, Susan Kling Finston and Samit Chattopadhyay _

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Oncotarget. 2018; 9:21322-21336. https://doi.org/10.18632/oncotarget.25093

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Abstract

Nandaraj Taye1, Aftab Alam1, Suvankar Ghorai2, Deya Ghosh Chatterji3, Apoorva Parulekar1, Devraj Mogare1, Snahlata Singh1, Pallabi Sengupta5, Subhrangsu Chatterjee5, Manoj Kumar Bhat1, Manas Kumar Santra1, Prabhakar Budha Salunkhe6, Susan Kling Finston6 and Samit Chattopadhyay1,4

1National Centre for Cell Science, Pune 411 007, India

2SRM University, Tamil Nadu, Kattankulathur 603 203, India

3NKP Salve Institute of Medical Sciences, Nagpur, 440 019, India

4Indian Institute of Chemical Biology (CSIR), West Bengal, Kolkata 700 032, India

5Department of Biophysics, Bose Institute, Kolkata 700 054, India

6Amrita Therapeutics Limited, Ahmedabad 380 054, India

Correspondence to:

Samit Chattopadhyay, email: samit@iicb.res.in

Keywords: β-catenin; conditioned medium; peptide; SMAR1; Wnt3a

Received: October 16, 2017     Accepted: March 21, 2018     Published: April 20, 2018

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 mask the D-box elements of SMAR1. These peptides stabilized SMAR1 expression that further inhibited metastatic SW480 colorectal cancer cell migration and invasion. Drastically reduced subcutaneous tumors were observed in in-vivo NOD-SCID mice upon administration of these peptides (25 mg/kg body weight) intraperitoneally. Taken together our structural studies, in-vitro and in-vivo results strongly suggest that the D-box elements of SMAR1 represent novel druggable targets, where the microbial peptides hold promise as novel colorectal cancer therapeutics.


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