Therapeutic targeting of SETD2-deficient cancer cells with the small-molecule compound RITA

Abstract The histone methyltransferase SETD2 and its associated histone mark H3 lysine 36 trimethylation (H3K36me3) are frequently lost in cancer, identifying SETD2 tumour suppressor loss as an important therapeutic target. Here we show that SETD2-deficient cancer cells are profoundly sensitive to RITA (2,5-bis[5-hydroxymethyl-2-thienyl] furan; NSC652287). Exposure of SETD2-deficient cancer cells to RITA results in significant p53 induction and apoptosis. However, TP53-deficient cells also exhibit RITA sensitivity suggesting p53 induction is an effect rather than a cause of RITA sensitivity. We find that RITA sensitivity is dependent on the phenol sulfotransferase SULT1A1, which is highly upregulated in SETD2-deficient cells. Accordingly, structural modifications of RITA, predicted to compromise its sulfation, ablated its activity. Further, SETD2-deficient cells can be targeted with YC-1, another SULT1A1-dependent anti-cancer agent. RITA sensitivity was associated with defects in DNA replication, leading to delays in S-phase progression, increased recruitment of replication stress markers, and reduced replication fork progression. Consistent with this, global target deconvolution using thermal profiling (2D-TPP) identified a broad range of RITA target proteins, including many involved in DNA replication stress. Together, these findings support the exploitation of SULT1A1 expression as a novel therapeutic strategy to target SETD2-deficient cancers.