Abstract
Mounting evidence points to alterations in mitochondrial metabolism in renal cell carcinoma (RCC). However, the mechanisms that regulate the TCA cycle in RCC remain uncharacterized. Here, we demonstrate that loss of TCA cycle enzyme expression is retained in RCC metastatic tissues. Moreover, proteomic analysis demonstrates that reduced TCA cycle enzyme expression is far more pronounced in RCC relative to other tumor types. Loss of TCA cycle enzyme expression is correlated with reduced expression of the transcription factor PGC-1α, which is also lost in RCC tissues. PGC-1α reexpression in RCC cells restores the expression of TCA cycle enzymes in vitro and in vivo and leads to enhanced glucose carbon incorporation into TCA cycle intermediates. Mechanistically, TGF-β signaling, in concert with histone deacetylase 7 (HDAC7), suppresses TCA cycle enzyme expression. Our studies show that pharmacologic inhibition of TGF-β restores the expression of TCA cycle enzymes and suppresses tumor growth in an orthotopic model of RCC. Taken together, this investigation reveals a potentially novel role for the TGF-β/HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provides insight into the molecular basis of altered mitochondrial metabolism in this malignancy.
Highlights
Clear cell renal cell carcinoma is the most common histologic subtype of kidney cancer
An established sequelae of VHL loss leads to the stabilization of hypoxia inducible factors (HIFs) which has been linked with alterations in mitochondrial metabolism [16]
We found that the mRNA expression of TCA cycle enzymes is reduced in metastatic tissues indicating that the pronounced shift in TCA cycle metabolism is retained with tumor progression (Figure 1E)
Summary
Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of kidney cancer. 30% to 40% of patients with ccRCC present with metastases at initial diagnosis [1, 2]. A better understanding of the factors leading to tumor progression in RCC and the development of novel therapeutic strategies are of potential significance. The most-well characterized is increased expression of glycolytic genes that results from loss/mutation of VHL, a common tumor initiating event. Loss of the E3 ubiquitin ligase activity of VHL results in stabilization of the hypoxia inducible factors (HIFs) and subsequent upregulation of hypoxia-responsive genes [3,4,5]. Glycolytic enzymes are known HIF transcriptional targets in cancer [6, 7]
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