2--3--4--trihydroxyflavone and Neoplasms

SUMOylation is a key post-translational modification that involves the covalent attachment of small ubiquitin-like modifier (SUMO) to the lysine residues of target proteins. The well-balanced SUMOylation is essential for normal cellular behaviors, while disturbance of SUMOylation is associated with various cancers and other diseases. Herein, we summarize the structures and biological functions of proteins involved in the SUMOylation process, their dysregulation in human diseases, and the discovery of small-molecular inhibitors targeting this pathway. In addition, we highlight the emerging trends in this field.

Topics: Humans; Neoplasms; Protein Processing, Post-Translational; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin

Human single-stranded DNA-binding protein 1 (hSSB1) is required for the efficient recruitment of the MRN complex to DNA double-strand breaks and is essential for the maintenance of genome integrity. However, the mechanism by which hSSB1 recruits NBS1 remains elusive. Here, we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage. SUMOylation of hSSB1, which is specifically fine-tuned by PIAS2α, and SENP2, not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites. Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation, and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide. Our findings reveal that SUMOylation, as a novel posttranslational modification of hSSB1, is critical for the functions of this protein, indicating that the use of SUMOylation inhibitors (e.g., 2-D08 and ML-792) may be a new strategy that would benefit cancer patients being treated with chemo- or radiotherapy.

Topics: Cysteine Endopeptidases; DNA Breaks, Double-Stranded; DNA Damage; Esters; Flavones; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Inhibitors of Activated STAT; Protein Processing, Post-Translational; Pyrazoles; Pyrimidines; Radiation, Ionizing; Sulfonic Acids; Sumoylation; Suppressor of Cytokine Signaling Proteins; Ubiquitin-Conjugating Enzymes