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Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor.

Abstract：

:Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors. Using ML-792, we further explored the critical roles of SUMOylation in mitotic progression and chromosome segregation. Furthermore, expression of an SAE catalytic-subunit (UBA2) S95N M97T mutant rescued SUMOylation loss and the mitotic defect induced by ML-792, thus confirming the selectivity of ML-792. As a potent and selective SAE inhibitor, ML-792 provides rapid loss of endogenously SUMOylated proteins, thereby facilitating novel insights into SUMO biology.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

He X,Riceberg J,Soucy T,Koenig E,Minissale J,Gallery M,Bernard H,Yang X,Liao H,Rabino C,Shah P,Xega K,Yan ZH,Sintchak M,Bradley J,Xu H,Duffey M,England D,Mizutani H,Hu Z,Guo J,Chau R,Dick LR,Brownell JE,Ne

doi

10.1038/nchembio.2463

subject

Has Abstract

pub_date

2017-11-01 00:00:00

pages

1164-1171

issue

11

eissn

1552-4450

issn

1552-4469

pii

nchembio.2463

journal_volume

13

pub_type

杂志文章

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