The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling.

Shaheen Sikandar,Zuomei Li,Xiling Shen,Diana Dizon,Steven M Lipkin,Jeffery Besterman

doi:10.18632/oncotarget.194

Shaheen Sikandar, Zuomei Li + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.194

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Abstract

Colorectal cancer metastatic recurrence and chemoresistance are major causes of morbidity and mortality. Colon cancer initiating cells (CCIC) are thought to contribute to both these processes. To identify drugs with anti-CCIC activity we screened a number of FDA approved and investigational compounds. We found that the class I selective histone deacetylase inhibitor (HDACi) MGCD0103 has significant activity against CCIC, and also significantly inhibits non-CCIC CRC cell xenograft formation. Both MGCD0103 and the pan-HDAC inhibitor Trichostatin impairs CCIC clonogenicity and cause cell cycle arrest and cell death. Gene expression profiling revealed that the canonical WNT ligand DKK-1 is a highly upregulated target of HDAC inhibitors. Despite the presence of APC mutations and constitutive WNT signaling in CCIC, both transfected and recombinant DKK-1 dramatically inhibit CCIC proliferation and clonogenicity. Overall, these data show that inhibition of class I HDACs is a promising novel approach to target both CCIC and non-CCIC CRC cells. Our studies also provide novel insights into roles for DKK1 in addition to canonical WNT signaling and the mechanism of CCIC tumor formation.

Highlights

Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States
To test if Histone deacetylases (HDACs) inhibitors have anti-tumor capacity in colon cancer we tested if Class I HDAC inhibitor MGCD0103 and TSA affected proliferation in colon cancer cell lines
We found that MGCD0103 had antiproliferative activity against colon cancer cell lines in MTT assays with an IC50 value of 0.7-1.0μM in Concentration of MGCD0103

Summary

Introduction

Colorectal cancer (CRC) is the 2nd leading cause of cancer death in the United States. MGCD0103 is active against commonly used non-CCIC CRC cell lines These data were confirmed with the non-class specific HDACi Trichostatin (TSA). Our data show that MGCD0103 is a promising approach to target CCIC as well as non-CCIC CRC cells This dual activity is important because CCIC are highly chemoresistant. Our data provide evidence that DKK-1 can inhibit proliferation and clonogenicity even in CCIC that carry APC mutations This result is consistent with a role for DKK1 to inhibit CCIC growth through mechanisms in addition to its role in canonical WNT signaling pathways and provides insight into the mechanisms of CCIC proliferation, tumor formation and chemoresistance

Results

C DKK-1 expression on TSA treatment

Materials and Methods