Inhibiting SUMO1-mediated SUMOylation induces autophagy-mediated cancer cell death and reduces tumour cell invasion via RAC1

Abstract

Post-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 tumourigenic 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 autophagymediated cancer cell death by increasing the expression of Tribbles pseudokinase 3. 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.

Las modificaciones postraduccionales son uno de los mecanismos de regulación más importantes en organismos eucariotas. La modificación por SUMOilación implica la unión covalente de un péptido, SUMO (Small Ubiquitin-related Modifier), a un residuo lisina en una proteína diana. En este trabajo mostramos como el bloqueo de la vía SUMO, mediante depleción genética de componentes de la ruta de SUMOilación, o mediante el uso de dos inhibidores de SUMOilación (GA o 2-D08), inhibe la tumorigénesis por dos mecanismos diferentes: (i) estimulación de la muerte celular mediada por autofagia a través de la inducción de TRIB3; y (ii) bloqueo de la invasividad tumoral mediante inhibición de la SUMOilación de la pequeña GTPasa RAC1.