Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence.
Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence.
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DOI：
10.1158/0008-5472.can-17-1536
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发表时间：
2017-12-15
期刊：
影响因子：
11.2
通讯作者：
Hemler ME
中科院分区：
文献类型：
--
作者：
Sharma C;Wang HX;Li Q;Knoblich K;Reisenbichler ES;Richardson AL;Hemler ME
dhhc型蛋白酰基转移酶可能调节其底物的定位、稳定性和/或活性。在这项研究中，我们发现蛋白棕榈酰转移酶DHHC3在恶性和转移性人乳腺癌中上调。在乳腺癌和其他六种人类癌症中，DHHC3表达升高与患者生存率降低相关。ZDHHC3消融术在人MDA-MB-231乳腺肿瘤细胞异种移植物中减少原发肿瘤和转移性肺菌落的大小。基因阵列数据和荧光染料分析显示，zdhhc3消融细胞氧化应激和衰老增加。zdhhc3消融的肿瘤还显示先天免疫细胞（抗肿瘤巨噬细胞、自然杀伤细胞）的募集增强，与衰老肿瘤的清除有关。这些抗肿瘤作用在野生型重组后被逆转，但在酶活性位点缺陷的DHHC3重组后则不被逆转。同时消融上调的氧化应激蛋白TXNIP，实质上否定了ZDHHC3缺失对氧化应激和衰老的影响。dhhc3依赖性棕榈酰化降低的ERGIC3蛋白可能在TXNIP上调中起关键作用。总之，dhhc3介导的蛋白棕榈酰化通过调节细胞氧化应激和衰老来支持乳腺肿瘤的生长。
DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (antitumor macrophages, natural killer cells) associated with clearance of senescent tumors. These antitumor effects were reversed upon reconstitution with wild-type, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.