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

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.

Exercise‐induced changes in tumour LDH‐B and MCT1 expression are modulated by oestrogen‐related receptor alpha in breast cancer‐bearing BALB/c mice

“…; Mirebeau‐Prunier et al . ). In breast cancer, the activation of aerobic glycolysis by the ERRα–PGC1β complex plays an important role in sustaining energy needs during tumorgenesis (Eichner et al .…”

“…have demonstrated an inverse correlation between ERRα expression and LDH activity and suggested an important role for ERRα in the induction of a metabolic shift in thyroid cells (Mirebeau‐Prunier et al . ). ERRα is primarily assumed to regulate energy homeostasis via interaction with the peroxisome proliferator‐activated receptor γ co‐activator‐1α and ‐1β (PGC‐1α and ‐1β; Huss et al .…”

miR-200b is a key regulator of tumor progression and metabolism targeting lactate dehydrogenase A in human malignant glioma

“…Among all the glycolytic enzymes, LDH is of great importance to maintain high glycolysis rate. And LDHA is reported to be up-regulated in many cancers [16, 17, 19–21, 23]. …”

There and back again: The journey of the estrogen-related receptors in the cancer realm

“…Conversely, ERRa activates the gene promoters of glycolytic enzymes in breast cancer to maintain aerobic glycolysis and support proliferation by meeting the energy demands of dividing cells [53,55,56]. In contrast to these observations, negative regulation of lactate dehydrogenase activity by ERRa modulation of LDHB expression contributes to elevated oxidative metabolism in thyroid tumors [57]. Similarly, ERRa and PGC-1a collaborate to govern metabolic programs of melanoma tumors that exhibit high levels of mitochondrial energy metabolism instead of glycolysis [58].…”

“…In fact, important cell cycle regulators including RB and CDK4 themselves impact on metabolism [79]. ERRa modulates the expression of several of these regulators in breast cancer cells and in thyroid tumors [14,57,63], while splice variants of ERRb differentially mediate progression through cell cycle checkpoints [80]. ERRa, b, and g bind to and modulate the expression of p21 [81][82][83], a regulator of the G1/S checkpoint.…”