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 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.

Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy

“…Motivated by the observations that SUMOylated ANXA1 specifically promoted the degradation of IKKα but not IKKβ or IKKγ, we then investigated whether SUMOylation of ANXA1 promotes degradation through selective autophagy. SUMO-modified protein has been found to facilitate autophagy-dependent degradation of specific target proteins ( 29 ). Co-IP experiments between IKKα and several major cargo receptors, including OPTN, p62/SQSTM1, NBR1, NDP52, and TOLLIP, were then performed to determine the autophagic receptor of IKKα.…”

Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

“…These results suggest that SUMOylation promotes autophagy flux. By contrast, blocking the SUMO pathway by depleting SUMO1 and UBC9 or by exposure to ginkgolic acid (a SUMOylation inhibitor) enhances the autophagy flux in breast cancer cells [149]. Thus, SUMOylation can modulate autophagy in two opposite directions, depending on the cell/tissue type, regulator, and targets of the SUMO pathway being altered.…”

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

“…Small molecules modulators of deSUMOylation are actively searched [81,82]. Potent SENP-selective inhibitors are now emerging [83] as well as efficient SUMOylation inhibitors, like the anticancer trihydroxyflavone derivative 2-D08 [84][85][86]. A deregulation of the SUMO pathway has been observed in different cancers, such as breast cancer [87] and hepatocellular carcinoma [88].…”