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Abstract
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.
Highlights
The estrogen-related receptor alpha (ERRa) is an orphan nuclear receptor involved in the regulation of mitochondrial biogenesis through the oxidation of fats and glucose [1,2,3]
Tissues and Cell Lines We studied the expression of ERRa and lactate deshydrogenase (LDH) in 30 normal or tumoral human thyroid tissues and three human thyroid cancer cell lines: RO82W-1, FTC-133, XTC.UC1
Our findings indicate that ERRa may regulate anaerobic glycolysis via LDH activity in thyroid tumors
Summary
The estrogen-related receptor alpha (ERRa) is an orphan nuclear receptor involved in the regulation of mitochondrial biogenesis through the oxidation of fats and glucose [1,2,3]. ERRa binds to the ERR response element (ERRE) leading to the regulation of the cellular energy metabolism according to endogenous or exogenous stimuli [2,6,7]. This transcription factor may interfere with the three transcriptional coactivators of the PGC-1 family, i.e. the PPARc coactivator-1a (PGC-1a), the PPARc coactivator-1b (PGC-1b) and the PGC-1-related coactivator (PRC), all of which serve as mediators between the environment and the transcriptional machinery. We have shown that the ERRa-PRC transcriptional complex plays a consistent role in thyroid proliferative cells by increasing the coupling efficiency of mitochondria in oxidative cells, and through some other pathway in glycolytic cells [6]. The implication of PRC-ERRa complex in the direct regulation of key enzymes of the glycolytic pathway, such as lactate deshydrogenase (LDH), needs to be investigated
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