Targeting EHMT1/2 sensitizes colorectal cancer to pan-HDAC inhibitors

Here, we applied a functional genomics approach using pooled CRISPR/Cas9 screens to identify genes that sensitizes CRC to HDACi upon depletion. We developed a custom, focused sgRNA library targeting epigenetic regulators and identified the histone methyltransferases EHMT1 and EHMT2 as critical regulators of cellular response to HDACi. We found that EHMT2 expression in CRC tissues is significantly correlated with clinical outcome. Targeting of EHMT1/2 by small molecule inhibitors synergistically reduced proliferation of CRC cells in the presence of HDACi. Mechanistically, we found that EHMT and HDAC inhibitors elicit distinct cellular mechanisms to reduce tumor growth. Finally, we validated the synergistic effects of this drug combination in a panel of patient-derived CRC organoids.