PRMT1 inhibition induces differentiation of colon cancer cells

Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women with over 1.8 million new cases in 20181. Differentiation therapy has been recently revisited as a prospective approach in cancer therapy2 by targeting the aberrant growth, and repairing differentiation and cell death programs of cancer cells. Standard of care chemotherapy may kill cancer cells, but the aggressive cells can survive and resistance gradually develops. In contrast, differentiation therapy aims not to eradicate cancer bulk, but rather directs cancer cells towards inhibited proliferation and restoration of the apoptotic program, while maintaining a limited toxicity. Current data suggests that differentiation therapy can be an effective anti-cancer treatment approach, however discovery of the new differentiation inducing molecules with a higher therapeutic index is essential. We performed High Throughput Screening (HTS) for discovery of compounds, which induce differentiation of colon cancer cells, using a novel dual multiplex assay3. Here we show that MS023, arginine methyl transferase (PRMT) type 1 inhibitor, is a potent inducer of colon cancer cell differentiation with a large therapeutic window. Our findings have a great impact for future research and development of an effective, clinically applicable, differentiation based anti-CRC therapy. Overall design: 5790 compounds from different chemical libraries were screened at 10µM concentration for their ability to induce ALP activity and delay growth of HT-29 cells. RNA sequencing of HT-29 that were treated with either MS023, entiostat or DMSO(control) was done in quadruplicates, using Illumina Hi-seq 2500.