Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3
Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3
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DOI：
10.1042/bj20081132
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发表时间：
2009-01-01
影响因子：
4.1
通讯作者：
Ganapathy, Vadivel
中科院分区：
文献类型：
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作者：
Thangaraju, Muthusamy;Carswell, Kristina N.;Ganapathy, Vadivel
人类结肠癌细胞和原发性结肠癌沉默编码LDH（乳酸脱氢酶）-B的基因并上调编码LDH-A的文件基因，导致丙酮酸有效转化为乳酸。这与癌症细胞中丙酮酸水平与非恶性细胞相比显着降低有关。癌细胞中 LDH-B 的沉默是通过 DNA 甲基化发生的，其中涉及 DNMT（DNA 甲基转移酶）DNMT1 和 DNMT3b。结肠癌还与丙酮酸激酶 M2 的表达有关，丙酮酸激酶 M2 是一种催化活性较低的剪接变体。我们最近证明丙酮酸是 HDAC（组蛋白脱乙酰酶）的抑制剂。在这里，我们证明丙酮酸是 HDAC1 和 HDAC3 的特异性抑制剂。乳酸对所检查的任何 HDAC 均没有影响。与非恶性细胞相比，结肠癌细胞表现出 HDAC 活性增加。 HDAC1 和 HDAC3 在结肠癌细胞和原发性结肠癌中上调，并且 siRNA（小干扰 RNA）介导的结肠癌细胞中 HDAC1 和 HDAC3 的沉默会诱导细胞凋亡。结肠癌细胞沉默 SLC5A8，即编码 Na+ 偶联丙酮酸转运蛋白的基因。当在丙酮酸存在下培养时，人结肠癌细胞系 SW480 中 SLC5A8 的异源表达会导致 HDAC 活性受到抑制。该过程与细胞内丙酮酸水平的增加、历史H4乙酰化状态的增加以及细胞死亡的增加有关。这些研究表明，癌细胞有效地维持低水平的丙酮酸，以防止 HDAC1/HDAC3 的抑制，从而逃避细胞死亡。
Human colon cancer cells and primary colon cancer silence the gene coding for LDH (lactate dehydrogenase)-B and up-regulate file gene coding for LDH-A, resulting in effective conversion of pyruvate into lactate. This is associated with markedly reduced levels Of pyruvate in cancer, cells compared with non-malignant cells. The silencing of LDH-B in cancer cells occurs via DNA methylation, with involvement of the DNMTs(DNA methyltransferases) DNMT1 and DNMT3b. Colon cancer is also associated with the expression of pyruvate kinase M2, a splice variant with low catalytic activity. We have shown recently that pyruvate is an inhibitor of HDACs (histone deacetylases). Here we show that pyruvate is a specific inhibitor of HDAC1 and HDAC3. Lactate has no effect on any of the HDACs examined. Colon cancer cells exhibit, increased HDAC activity compared with non-malignant cells. HDAC1 and HDAC3 are up-regulated in colon cancer cells and in primary colon cancer, and siRNA (small interfering RNA)mediated silencing of HDAC1 and HDAC3 in colon cancer cells induces apoptosis. Colon cancer cells silence SLC5A8, the gene coding for it Na+-coupled pyruvate transporter. Heterologous expression of SLC5A8 in the human colon cancer cell line SW480 leads to inhibition of HDAC activity when cultured in the presence of pyruvate. This process is associated with ail increase in intracellular levels of pyruvate, increase in the acetylation Status of historic H4, and enhanced cell death. These Studies show that cancer cells effectively maintain low levels of pyruvate to prevent inhibition of HDAC1/HDAC3 and thereby to evade cell death.