c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent
manner, regulated by PIAS1, SENP7 and RNF4
#MMPMID25895136
González-Prieto R
; Cuijpers SA
; Kumar R
; Hendriks IA
; Vertegaal AC
Cell Cycle
2015[]; 14
(12
): 1859-72
PMID25895136
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c-Myc is the most frequently overexpressed oncogene in tumors, including breast
cancer, colon cancer and lung cancer. Post-translational modifications comprising
phosphorylation, acetylation and ubiquitylation regulate the activity of c-Myc.
Recently, it was shown that c-Myc-driven tumors are strongly dependent on the
SUMO pathway. Currently, the relevant SUMO target proteins in this pathway are
unknown. Here we show that c-Myc is a target protein for SUMOylation, and that
SUMOylated c-Myc is subsequently ubiquitylated and degraded by the proteasome.
SUMO chains appeared to be dispensable for this process, polymerization-deficient
SUMO mutants supported proteolysis of SUMOylated c-Myc. These results indicate
that multiple SUMO monomers conjugated to c-Myc could be sufficient to direct
SUMOylated c-Myc to the ubiquitin-proteasome pathway. Knocking down the
SUMO-targeted ubiquitin ligase RNF4 enhanced the levels of SUMOylated c-Myc,
indicating that RNF4 could recognize a multi-SUMOylated protein as a substrate in
addition to poly-SUMOylated proteins. Knocking down the SUMO E3 ligase PIAS1
resulted in reduced c-Myc SUMOylation and increased c-Myc transcriptional
activity, indicating that PIAS1 mediates c-Myc SUMOylation. Increased SUMOylation
of c-Myc was noted upon knockdown of the SUMO protease SENP7, indicating that it
also could regulate a multi-SUMOylated protein in addition to poly-SUMOylated
proteins. C-Myc lacks KxE-type SUMOylation consensus motifs. We used mass
spectrometry to identify 10 SUMO acceptor lysines: K52, K148, K157, K317, K323,
K326, K389, K392, K398 and K430. Intriguingly, mutating all 10 SUMO acceptor
lysines did not reduce c-Myc SUMOylation, suggesting that SUMO acceptor lysines
in c-Myc act promiscuously. Our results provide novel insight into the complexity
of c-Myc post-translational regulation.
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