Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

Summary Many solid cancers have an expanded CD44+/hi/CD24−/low cancer stem cell (CSC) population, which are relatively chemoresistant and drive recurrence and metastasis. Achieving a more durable response requires the development of therapies that specifically target CSCs. Recent evidence indicated that inhibiting the SUMO pathway repressed tumor growth and invasiveness, although the mechanism has yet to be clarified. Here, we demonstrate that inhibition of the SUMO pathway repressed MMP14 and CD44 with a concomitant reduction in cell invasiveness and functional loss of CSCs in basal breast cancer. Similar effects were demonstrated with a panel of E1 and E3 SUMO inhibitors. Identical results were obtained in a colorectal cancer cell line and primary colon cancer cells. In both breast and colon cancer, SUMO-unconjugated TFAP2A mediated the effects of SUMO inhibition. These data support the development of SUMO inhibitors as an approach to specifically target the CSC population in breast and colorectal cancer.
Highlights • Sumoylation regulates CD44 and MMP14 expression in basal breast and colon cancer • SUMO inhibition clears cancer stem cells, repressing invasiveness and tumor growth • Anacardic acid functions as a SUMO inhibitor to repress cancer stem cells • TFAP2A mediates anti-tumor effects of SUMO inhibition in breast and colon cancers
Weigel and colleagues provide substantial evidence for developing cancer stem cell-specific therapy based on inhibiting the SUMO pathway. They show that inhibition of sumoylation enzymes by knockdown or small-molecule inhibitors repressed cancer stem cells with loss of CD44 and MMP14, and reduced invasiveness and inhibition of tumor growth. Common SUMO-sensitive mechanisms were dependent upon TFAP2A in breast and colon cancer.