Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells.
Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells.
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DOI：
10.1016/j.neo.2018.08.006
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Nakamura Y
中科院分区：
文献类型：
--
作者：
Deng B;Tarhan YE;Ueda K;Ren L;Katagiri T;Park JH;Nakamura Y
蛋白质O-糖基化在包括乳腺癌在内的多种人类癌症中的改变是众所周知的，但其异常糖基化在癌症中的分子作用尚未完全了解。我们先前报道了多肽N-乙酰氨基半乳糖转移酶6（GALNT 6或GalNAc-T6）的关键作用，其在绝大多数乳腺癌组织中上调。在这里，我们进一步报告了GALNT 6对雌激素受体α（ER-α）的O-糖基化及其在乳腺癌细胞核定位中的重要作用。在ER-α和GALNT 6均高表达的乳腺癌细胞系T47 D和MCF 7中，用小干扰RNA（siRNA）敲低GALNT 6的表达可显著降低ER-α的表达。免疫细胞化学分析清楚地表明，ER-α蛋白在这些癌细胞的核中急剧减少。因此，ER-α通路的下游基因如MYC、CCND 1和CTSD显著下调。我们证实了GALNT 6依赖性ER-α O-糖基化，并通过LC-MS/MS分析鉴定了GALNT 6对ER-α F结构域中S573的O-糖基化。我们还发现GALNT 6对ER-α S573位点的糖基化对ER-α在乳腺癌细胞中的蛋白质稳定性和核定位至关重要。此外，我们设计了包括O-糖基化位点的细胞膜可渗透肽，并发现通过以GALNT 6表达依赖性方式处理这些肽，乳腺癌细胞的细胞活力显著降低。我们的研究表明，靶向GALNT 6酶活性以及GALNT 6/ER-α相互作用可能是ER-α阳性乳腺癌患者的一种有前途的治疗方法。
Alteration of protein O-glycosylation in various human cancers including breast cancer is well known, but molecular roles of their aberrant glycosylations on cancer have not been fully understood. We previously reported critical roles of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6 or GalNAc-T6) that was upregulated in a great majority of breast cancer tissues. Here we further report O-glycosylation of estrogen receptor alpha (ER-α) by GALNT6 and the significant role of its nuclear localization in breast cancer cells. Knockdown of GALNT6 expression in two breast cancer cell lines, T47D and MCF7, in which both ER-α and GALNT6 were highly expressed, by small interfering RNA could significantly attenuate expression of ER-α. Immunocytochemical analysis clearly demonstrated the drastic decrease of ER-α protein in the nucleus of these cancer cells. Accordingly, the downstream genes of the ER-α pathway such as MYC, CCND1, and CTSD were significantly downregulated. We confirmed GALNT6-dependent ER-α O-glycosylation and identified O-glycosylation of S573 in an F domain of ER-α by GALNT6 through LC-MS/MS analysis. We also obtained evidences showing that the glycosylation of ER-α at S573 by GALNT6 is essential for protein stability and nuclear localization of ER-α in breast cancer cells. Furthermore, we designed cell membrane–permeable peptides including the O-glycosylation site and found a significant decrease of the cell viability of breast cancer cells by treatment of these peptides in a GALNT6 expression–dependent manner. Our study suggests that targeting the GALNT6 enzymatic activity as well as the GALNT6/ER-α interaction could be a promising therapeutic approach to ER-α–positive breast cancer patients.
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影响因子：
11.5
作者：
Johnston, Stephen R. D.
通讯作者：
Johnston, Stephen R. D.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
胃癌中多肽N-乙酰半乳糖氨基转移酶6的表达
影响因子：
4
作者：
Guo Y;Shi J;Zhang J;Li H;Liu B;Guo H
通讯作者：
Guo H
他莫昔芬在乳腺癌中的分子机制和模式。
影响因子：
1.9
作者：
Ali S;Rasool M;Chaoudhry H;N Pushparaj P;Jha P;Hafiz A;Mahfooz M;Abdus Sami G;Azhar Kamal M;Bashir S;Ali A;Sarwar Jamal M
通讯作者：
Sarwar Jamal M
影响因子：
51.1
作者：
Derks, Marloes G. M.;Blok, Erik J.;van de Velde, Cornelis J. H.
通讯作者：
van de Velde, Cornelis J. H.