ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.
ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.
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DOI：
10.1093/nar/gkv026
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发表时间：
2015-02-18
影响因子：
14.9
通讯作者：
Hur MW
中科院分区：
文献类型：
--
作者：
Kim MY;Koh DI;Choi WI;Jeon BN;Jeong DY;Kim KS;Kim K;Kim SH;Hur MW
NF-κB存在于几乎所有的动物细胞类型中，并参与无数的细胞反应。NF-κB的异常表达与癌症、炎性疾病和发育不良有关。NF-κB家族成员基因RelA/p65的转录调控机制目前知之甚少。Sp1在RelA/p65基因的表达中起关键作用。ZBTB 2通过抑制Sp1与RelA/p65近端启动子（bp，−31至−21）中Sp1结合GC盒的结合来抑制基因的转录。此外，最近的研究表明，RelA/p65直接结合过氧化物酶体增殖物激活受体-γ共激活因子1 α（PGC 1 α），以降低PGC 1 α靶基因PDK 4的转录激活，PDK 4的基因产物抑制丙酮酸脱氢酶（PDH），这是TCA循环流量的关键调节因子。因此，我们观察到ZBTB 2对RelA/p65的抑制间接导致PDK 4表达增加，从而抑制PDH。因此，在具有异位ZBTB 2的细胞中，丙酮酸和乳酸的浓度高于正常细胞中的浓度，表明在TCA循环中有利于糖酵解的葡萄糖代谢通量的变化。在小鼠异种移植物中ZBTB 2的敲低降低了肿瘤生长。ZBTB 2可能通过抑制RelA/p65表达上调PDK 4表达，重新编程葡萄糖代谢途径以促进糖酵解，从而增加细胞增殖。
The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, −31 to −21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.
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