Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1
Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1
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DOI：
10.1038/onc.2010.41
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发表时间：
2010-05-01
期刊：
影响因子：
8
通讯作者：
Reginato, M. J.
中科院分区：
文献类型：
--
作者：
Caldwell, S. A.;Jackson, S. R.;Reginato, M. J.
癌细胞上调糖酵解，增加葡萄糖摄取以满足能量需求。一小部分细胞的葡萄糖进入己糖胺生物合成途径（HBP），其调节O-连接的β-N-乙酰葡糖胺（O-GlcNAc）的水平，这是多种核和胞质蛋白的碳水化合物翻译后修饰。我们发现乳腺癌细胞上调HBP，包括增加的O-GlcNAc化和升高的O-GlcNAc转移酶（OGT）表达，O-GlcNAc转移酶是催化O-GlcNAc添加到蛋白质的酶。通过RNA干扰乳腺癌细胞中的OGT减少O-GlcNAc化导致体外和体内肿瘤生长的抑制，并与细胞周期进展减少和细胞周期抑制剂p27（Kip 1）表达增加相关。p27（Kip 1）的升高与致癌转录因子FoxM 1的表达和活性降低相关，FoxM 1是一种已知的通过Skp 2转录控制p27（Kip 1）稳定性的调节因子。降低乳腺癌细胞中的O-GlcNAc水平会降低FoxM 1蛋白的水平，并导致包括Skp 2在内的多种FoxM 1特异性靶点的减少。此外，减少O-GlcNAc化降低了癌细胞的侵袭，并与基质金属蛋白酶-2（一种已知的FoxM 1靶标）的下调有关。最后，药理学抑制OGT在乳腺癌细胞中具有类似的抗生长和抗侵袭作用。这些研究结果确定O-GlcNAc作为一种新的机制，通过这种机制，葡萄糖代谢的改变调节癌症的生长和侵袭，并表明OGT可能代表乳腺癌的新的治疗靶点。Oncogene（2010）29，2831-2842; doi：10.1038/onc.2010.41; 2010年3月1日在线发表
Cancer cells upregulate glycolysis, increasing glucose uptake to meet energy needs. A small fraction of a cell's glucose enters the hexosamine biosynthetic pathway (HBP), which regulates levels of O-linked beta-N-acetylglucosamine (O-GlcNAc), a carbohydrate posttranslational modification of diverse nuclear and cytosolic proteins. We discovered that breast cancer cells upregulate the HBP, including increased O-GlcNAcation and elevated expression of O-GlcNAc transferase (OGT), which is the enzyme catalyzing the addition of O-GlcNAc to proteins. Reduction of O-GlcNAcation through RNA interference of OGT in breast cancer cells leads to inhibition of tumor growth both in vitro and in vivo and is associated with decreased cell-cycle progression and increased expression of the cell-cycle inhibitor p27(Kip1). Elevation of p27(Kip1) was associated with decreased expression and activity of the oncogenic transcription factor FoxM1, a known regulator of p27(Kip1) stability through transcriptional control of Skp2. Reducing O-GlcNAc levels in breast cancer cells decreased levels of FoxM1 protein and caused a decrease in multiple FoxM1-specific targets, including Skp2. Moreover, reducing O-GlcNAcation decreased cancer cell invasion and was associated with the downregulation of matrix metallo-proteinase- 2, a known FoxM1 target. Finally, pharmacological inhibition of OGT in breast cancer cells had similar anti-growth and anti-invasion effects. These findings identify O-GlcNAc as a novel mechanism through which alterations in glucose metabolism regulate cancer growth and invasion and suggest that OGT may represent novel therapeutic targets for breast cancer. Oncogene (2010) 29, 2831-2842; doi: 10.1038/onc.2010.41; published online 1 March 2010