Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment of differentiation.
Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment of differentiation.
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DOI：
10.3389/fendo.2022.932286
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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2-羟基戊二酸(2HG)在包括肾脏在内的许多组织中都会产生过多的肿瘤。2HG的过度生产导致肿瘤的发生归因于2HG通过抑制依赖于α-酮戊二酸(α-KG)的双加氧酶，包括Ten-11-易位(Tet)酶来改变基因表达的能力。据报道，调节细胞分化的基因被抑制，阻止间充质细胞分化为肌细胞和脂肪细胞。本文利用慢病毒shRNA和siRNA，在原代培养的正常肾小管上皮细胞中，下调了导致L2HG降解的酶--L-2HG脱氢酶(L2HGDH)的表达。基因敲除(KD)导致L-2HG水平升高，基因组DNA 5mC去甲基化减少，H3组蛋白甲基化增加。结果包括RPT细胞在Matrigel中的小管生成减少，分化分子标记的表达减少，包括膜转运蛋白以及调节其转录的HNF1α和HNF1β。这些结果与肿瘤代谢物2HG通过改变染色质甲基化状态从而阻止正常分化所需的转录事件而阻止RPT分化的假设是一致的。据推测，类似的变化也促进了肾癌干细胞的扩张，增加了它们恶变的倾向。
2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, including the kidney. The tumorigenesis resulting from overproduced 2HG has been attributed to the ability of 2HG alter gene expression by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation (TET) enzymes. Genes that regulate cellular differentiation are reportedly repressed, blocking differentiation of mesenchymal cells into myocytes, and adipocytes. In this report, the expression of the enzyme responsible for L2HG degradation, L-2HG dehydrogenase (L2HGDH), is knocked down, using lentiviral shRNA, as well as siRNA, in primary cultures of normal Renal Proximal Tubule (RPT) cells. The knockdown (KD) results in increased L-2HG levels, decreased demethylation of 5mC in genomic DNA, and increased methylation of H3 Histones. Consequences include reduced tubulogenesis by RPT cells in matrigel, and reduced expression of molecular markers of differentiation, including membrane transporters as well as HNF1α and HNF1β, which regulate their transcription. These results are consistent with the hypothesis that oncometabolite 2HG blocks RPT differentiation by altering the methylation status of chromatin in a manner that impedes the transcriptional events required for normal differentiation. Presumably, similar alterations are responsible for promoting the expansion of renal cancer stem-cells, increasing their propensity for malignant transformation.
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影响因子：
--
作者：
Mancini M;Soverini S;Gugliotta G;Santucci MA;Rosti G;Cavo M;Martinelli G;Castagnetti F
通讯作者：
Castagnetti F
影响因子：
16.6
作者：
Kang Z;Zhang M;Gao K;Zhang W;Meng W;Liu Y;Xiao D;Guo S;Ma C;Gao C;Xu P
通讯作者：
Xu P
影响因子：
3.6
作者：
Kikuchi, Ryota;Kusuhara, Hiroyuki;Sugiyama, Yuichi
通讯作者：
Sugiyama, Yuichi
影响因子：
13.6
作者：
Hara-Chikuma, Mariko;Verkman, A. S.
通讯作者：
Verkman, A. S.
影响因子：
6.6
作者：
Ježek P
通讯作者：
Ježek P