Chemotherapeutic drugs used in the treatment of acute myeloid leukemias (AMLs) are thought to induce cancer cell death through the generation of DNA double-strand breaks. Here, we report that one of their early effects is the loss of conjugation of the ubiquitin-like protein SUMO from its targets via reactive oxygen species (ROS)-dependent inhibition of the SUMO-conjugating enzymes. Desumoylation regulates the expression of specific genes, such as the proapoptotic gene DDIT3, and helps induce apoptosis in chemosensitive AMLs. In contrast, chemotherapeutics do not activate the ROS/SUMO axis in chemoresistant cells. However, pro-oxidants or inhibition of the SUMO pathway by anacardic acid restores DDIT3 expression and apoptosis in chemoresistant cell lines and patient samples, including leukemic stem cells. Finally, inhibition of the SUMO pathway decreases tumor growth in mice xenografted with AML cells. Thus, targeting the ROS/SUMO axis might constitute a therapeutic strategy for AML patients resistant to conventional chemotherapies.

In recent genome-wide association studies, genetic variants in TCF7L2, SLC30A8, HHEX, LOC387761, and EXT2 were associated with risk for type 2 diabetes mellitus (T2DM). We aimed at investigating the association of these single-nucleotide polymorphisms (SNPs) with T2DM and defining their corresponding allelic and genotypic combinations in the Tunisian population. We also tried to determine the effect of R325W of SLC30A8 on the modeled structural properties of the protein. Five SNPs were genotyped in 331 T2DM Tunisian patients and 403 healthy subjects by polymerase chain reaction-restriction fragment length polymorphism. A model of residues 318-366 of the SLC30A8 protein was built by homology modeling. LOC387761 provided the strongest evidence for replication, where rs7480010 presented a risk of 2.41 with T2DM, followed by rs1111875 in HHEX (odds ratio=1.95) and rs13266634 in SLC30A8 (odds ratio=1.59). None of the two other SNPs previously reported was associated. The highest risk of T2DM was 3.1, obtained by the genotype combination of the three associated SNPs. Modeling of the cytoplasmic part of the SLC30A8 protein showed that the R325W change might affect the electrostatic potential of the SLC30A8 protein. We concluded that the SLC30A8, HHEX, and LOC387761 are more likely to represent the genuine signals of T2DM in the Tunisian population.

Colorectal cancer is one of the most commonly diagnosed cancers and the third most common cause of cancer-related death. Metastasis is the leading reason for the resultant mortality of these patients. Accordingly, development and characterization of novel anti-cancer drugs limiting colorectal tumor cell dissemination and metastasis are needed. In this study, we found that the small molecule Reversine reduces the migration potential of human colon carcinoma cells in vitro. A coupled kinase assay with bio-informatics approach identified the c-Jun N-terminal kinase (JNK) cascade as the main pathway inhibited by Reversine. Knockdown experiments and pharmacological inhibition identified JNK1 but not JNK2, as a downstream effector target in cancer cell migration. Xenograft experiments confirm the effect of JNK inhibition in the metastatic potential of colon cancer cells. These results highlight the impact of individual JNK isoforms in cancer cell metastasis and propose Reversine as a novel anti-cancer molecule for treatment of colon cancer patients.