Estrogen-Related Receptor Alpha Modulates Lactate Dehydrogenase Activity in Thyroid Tumors

Metabolic modifications of tumor cells are hallmarks of cancer. They exhibit an altered metabolism that allows them to sustain higher proliferation rates in hostile environment outside the cell. In thyroid tumors, the expression of the estrogen-related receptor α (ERRα), a major factor of metabolic adaptation, is closely related to the oxidative metabolism and the proliferative status of the cells. To elucidate the role played by ERRα in the glycolytic adaptation of tumor cells, we focused on the regulation of lactate dehydrogenases A and B (LDHA, LDHB) and the LDHA/LDHB ratio. Our study included tissue samples from 10 classical and 10 oncocytic variants of follicular thyroid tumors and 10 normal thyroid tissues, as well as samples from three human thyroid tumor cell lines: FTC-133, XTC.UC1 and RO82W-1. We identified multiple cis-acting promoter elements for ERRα, in both the LDHA and LDHB genes. The interaction between ERRα and LDH promoters was confirmed by chromatin immunoprecipitation assays and in vitro analysis for LDHB. Using knock-in and knock-out cellular models, we found an inverse correlation between ERRα expression and LDH activity. This suggests that thyroid tumor cells may reprogram their metabolic pathways through the up-regulation of ERRα by a process distinct from that proposed by the recently revisited Warburg hypothesis.

肿瘤细胞的代谢改变是癌症的标志性特征。此类细胞会发生代谢重编程，使其能够在细胞外的恶劣环境中维持更高的增殖速率。在甲状腺肿瘤中，代谢适应的关键调控因子——雌激素相关受体α（estrogen-related receptor α，ERRα）的表达，与细胞的氧化代谢及增殖状态密切相关。为阐明ERRα在肿瘤细胞糖酵解适应中发挥的作用，本研究聚焦于乳酸脱氢酶A、B（LDHA、LDHB）的调控以及LDHA/LDHB比值。本研究纳入了10例经典型滤泡状甲状腺肿瘤、10例嗜酸性变型滤泡状甲状腺肿瘤的组织样本，以及10例正常甲状腺组织样本，同时还使用了3株人甲状腺肿瘤细胞系：FTC-133、XTC.UC1与RO82W-1。我们在LDHA与LDHB基因的启动子区域中鉴定出多个ERRα结合的顺式作用元件。通过染色质免疫沉淀实验以及LDHB的体外分析，验证了ERRα与乳酸脱氢酶基因启动子的互作关系。借助敲入与敲除细胞模型，我们发现ERRα的表达水平与乳酸脱氢酶活性呈负相关。这提示甲状腺肿瘤细胞可通过上调ERRα的表达重编程其代谢通路，该过程不同于近年经重新审视的瓦伯格（Warburg）假说所提出的机制。