The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer.
The SIRT2 Deacetylase Stabilizes Slug to Control Malignancy of Basal-like Breast Cancer.
复制标题
SIRT2脱乙酰基酶稳定sl，以控制基底样乳腺癌的恶性肿瘤。
DOI：
10.1016/j.celrep.2016.10.006
复制
发表时间：
2016-10-25
期刊：
影响因子：
8.8
通讯作者：
Kuperwasser C
中科院分区：
文献类型：
--
作者：
Zhou W;Ni TK;Wronski A;Glass B;Skibinski A;Beck A;Kuperwasser C
Slug蛋白的过量在人类癌症中很常见，并且是基底样乳腺癌（BLBC）侵袭性的重要决定因素。尽管其重要性，这种转录因子很少在BLBC中突变，其在癌症中的失调机制仍然未知。在这里，我们报告鼻涕虫经历乙酰化依赖性蛋白质降解，并确定脱乙酰酶SIRT2作为这种翻译后机制的关键介质。SIRT2抑制迅速使Slug不稳定，而SIRT2过表达延长Slug稳定性。我们表明SIRT2在赖氨酸残基K116处使Slug蛋白脱乙酰基以防止Slug降解。有趣的是，SIRT2在BLBC中频繁扩增并高度表达。BLBC细胞中SIRT2的遗传缺失和药理学失活逆转了Slug稳定化，导致BLBC临床相关病理特征的丧失，并抑制肿瘤生长。我们的研究结果表明，靶向SIRT2可能是减少BLBC中Slug丰度及其相关恶性特征的合理策略。
Overabundance of Slug protein is common in human cancer and represents an important determinant underlying the aggressiveness of basal-like breast cancer (BLBC). Despite its importance, this transcription factor is rarely mutated in BLBC, and the mechanism of its deregulation in cancer remains unknown. Here we report that Slug undergoes acetylation-dependent protein degradation and identify the deacetylase SIRT2 as a key mediator of this post-translational mechanism. SIRT2 inhibition rapidly destabilizes Slug, whereas SIRT2 overexpression extends Slug stability. We show that SIRT2 deacetylates Slug protein at lysine residue K116 to prevent Slug degradation. Interestingly, SIRT2 is frequently amplified and highly expressed in BLBC. Genetic depletion and pharmacological inactivation of SIRT2 in BLBC cells reverse Slug stabilization, cause the loss of clinically relevant pathological features of BLBC, and inhibit tumor growth. Our results suggest that targeting SIRT2 may be a rational strategy for diminishing Slug abundance and its associated malignant traits in BLBC.
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影响因子：
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