A role for SUMO activating enzyme-2 in human cancer transformation models reveals regulation of self-renewal and induced differentiation

Cancer stem cells (CSCs) are a rare subset of tumor cells that initiate and sustain tumor regrowth and are associated with chemotherapy resistance leading to patient relapse. The molecular processes that endow CSCs with these unique behavioral characteristics are not fully understood. Post-translational modifications (PTMs), such as Small Ubiquitin-like Modifier (SUMO)-ylation, have emerged as one of several shared mechanisms across cancer subtypes also implicated in human CSC biology. Here, we investigated the role of SUMOylation by studying the E1-activating enzyme subunit, SUMO activating enzyme-2 (SAE2), in human models of CSCs and leukemia. Using loss- and gain-of-function strategies, we demonstrate that SAE2 is required and sufficient to sustain CSC self-renewal while its loss promotes differentiation. SAE2 overexpression enhances SUMOylation and stabilizes the central CSC mediator, OCT4 in the transformed-human pluripotent stem cell (t-hPSC) model, potentially by maintaining SAE2/OCT4/β-catenin axis. Knockdown of SAE2 in non-CSC lines such as OCI-AML3 leukemia cells activates AKT/ERK-mediated differentiation signaling leading to suppressed cell proliferation and reduced leukemic engraftment upon xenotransplantation. Our results indicate SAE2 as an important regulator of CSC biology in vitro and in vivo, with dissimilar roles in non-transformed human stem cells. These detailed observations suggest that targeting SAE2 and SUMOylated proteins may offer an attractive line of investigation into CSC regulation and understanding human cancer.