Abstract
SUMO (Small Ubiquitin-related MOdifier) is a post-translational modifier of the ubiquitin family controlling the function and fate of thousands of proteins. SUMOylation is deregulated in various hematological malignancies, where it participates in both tumorigenesis and cancer cell response to therapies. This is the case for Acute Promyelocytic Leukemias (APL) where SUMOylation, and subsequent destruction, of the PML-RARα fusion oncoprotein are triggered by arsenic trioxide, which is used as front-line therapy in combination with retinoic acid to cure APL patients. A similar arsenic-induced SUMO-dependent degradation was also documented for Tax, a human T-cell lymphotropic virus type I (HTLV1) viral protein implicated in Adult T-cell Leukemogenesis. SUMOylation also participates in Acute Myeloid Leukemia (AML) response to both chemo- and differentiation therapies, in particular through its ability to regulate gene expression. In Multiple Myeloma, many enzymes of the SUMO pathway are overexpressed and their high expression correlates with lower response to melphalan-based chemotherapies. B-cell lymphomas overexpressing the c-Myc oncogene also overexpress most components of the SUMO pathway and are highly sensitive to SUMOylation inhibition. Targeting the SUMO pathway with recently discovered pharmacological inhibitors, alone or in combination with current therapies, might therefore constitute a powerful strategy to improve the treatment of these cancers.
Highlights
In mammals, SUMO is a family of related ubiquitin-like peptidic post-translational modifiers, of which SUMO-1 to -3 are the best-studied members
Acute Myeloid Leukemia (AML) are a heterogenous group of severe hematological malignancies induced by oncogenic transformation of hematopoietic stem cells and myeloid progenitors
One exception concerns the Acute Promyelocytic Leukemia (APL) type of AMLs, which is efficiently cured using a differentiation therapy. It combines all-trans-retinoic acid (ATRA) and arsenic trioxide (As2O3 ), which leads to the degradation of the oncogene and restores the differentiation of the leukemic cells [51]
Summary
SUMO is a family of related ubiquitin-like peptidic post-translational modifiers (collectively called SUMO hereafter), of which SUMO-1 to -3 are the best-studied members. Reactive oxygen species (ROS) can inactivate SUMO conjugation by inducing the formation of a reversible disulfide bridge between SAE2/Uba and Ubc catalytic cysteines [30] This disrupts the SUMOylation/deSUMOylation cycle, resulting in cell protein deSUMOylation, which is required for survival under oxidative stress [31,32]. As many enzymes are involved in the SUMO conjugation/deconjugation cycle and as the number of SUMO targets and regulators is high, dysregulations of the SUMO system are expected to impact cellular behavior This could in turn facilitate the onset and progression of various human diseases, in particular cancer [34]. A missense mutation in the FANCA protein identified in a breast tumor was shown responsible for increased FANCA SUMOylation This triggers its RNF4-dependent ubiquitylation and degradation by the proteasome and, thereby, contributes to Fanconi anemia DNA repair pathway alteration [48]. They are reviewed hereafter in a context where promising pharmacological inhibitors targeting SUMOylation have recently been discovered and open novel therapeutic perspectives
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