Abstract
ABSTRACTPost-translational modifications directly control protein activity and, thus, they represent an important means to regulate the responses of cells to different stimuli. Protein SUMOylation has recently been recognised as one such modification, and it has been associated with various diseases, including different types of cancer. However, the precise way that changes in SUMOylation influence the tumorigenic properties of cells remains to be fully clarified. Here, we show that blocking the SUMO pathway by depleting SUMO1 and UBC9, or by exposure to ginkgolic acid C15:1 or 2-D08 (two different SUMOylation inhibitors), induces cell death, also inhibiting the invasiveness of tumour cells. Indeed, diminishing the formation of SUMO1 complexes induces autophagy-mediated cancer cell death through increasing the expression of Tribbles pseudokinase 3 (TRIB3). Moreover, we found that blocking the SUMO pathway inhibits tumour cell invasion by decreasing RAC1 SUMOylation. These findings shed new light on the mechanisms by which SUMO1 modifications regulate the survival, and the migratory and invasive capacity of tumour cells, potentially establishing the bases to develop novel anti-cancer treatments based on the inhibition of SUMOylation.
Highlights
The post-translational addition of the small ubiquitin-related modifier (SUMO) peptide is established as one of the key regulatory modifications in eukaryotic cells
Blocking the SUMO pathway inhibits cell viability in breast and prostate cancer cells As a first approach to investigate the effect of inhibiting the SUMO pathway on the tumorigenic properties of cancer cells, we analysed the effects of the natural compound Ginkgolic acids (GAs) C15:1, which blocks the SUMO pathway by inhibiting the formation of the E1–SUMO1 intermediate (Fukuda et al, 2009)
We identified the IC50 of GA as 10 μM in MDA-MB-231 cells and 20 μM in MCF7 cells
Summary
The post-translational addition of the small ubiquitin-related modifier (SUMO) peptide is established as one of the key regulatory modifications in eukaryotic cells. SUMOylation involves the reversible binding of a SUMO peptide to a lysine residue in the target protein and, to date, four different SUMO isoforms have been identified: SUMO1, SUMO2 and SUMO3 (denoted SUMO2/3 because they have a high degree of similarity), and SUMO4 Received 8 May 2019; Accepted 18 September 2019 and Hinchey, 2000) The addition of these peptides is mediated by an enzyme cascade that includes an activating enzyme (heterodimer SAE1/2), an E2-conjugating enzyme (UBC9) and an E3 ligase (RANBP2 from the SIZ/PIAS family and members of the ZNF451 family) (Hay, 2005; Pichler et al, 2017), and the substrates can be modified by adding a single SUMO moiety, multiple SUMOs or SUMO chains (Pichler et al, 2017). Interfering with the SUMOylation machinery could represent a novel therapeutic approach in the management of some diseases
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