RT Journal Article
SR Electronic
T1 TGF-β signaling suppresses TCA cycle metabolism in renal cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.19.429599
DO 10.1101/2021.02.19.429599
A1 Hyeyoung Nam
A1 Anirban Kundu
A1 Suman Karki
A1 Garrett Brinkley
A1 Darshan S. Chandrashekar
A1 Richard L. Kirkman
A1 Juan Liu
A1 Maria V. Liberti
A1 Jason W. Locasale
A1 Tanecia Mitchell
A1 Sooryanarayana Varambally
A1 Sunil Sudarshan
YR 2021
UL http://biorxiv.org/content/early/2021/02/19/2021.02.19.429599.abstract
AB The Warburg effect is one of most-well studied metabolic phenomenon in cancer cells. For the most part, these studies have focused on enhanced rates of glycolysis observed in various models. The presumption has been that mitochondrial metabolism is suppressed. However, recent studies indicate that the extent of mitochondrial metabolism is far more heterogeneous in tumors than originally presumed. One tumor type with suppression of mitochondrial metabolism is renal cell carcinoma (RCC). Prior studies indicate that suppressed TCA cycle enzyme mRNA expression is associated with aggressive RCC. Yet, 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 peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) which is also lost in RCC tissues. PGC-1α re-expression 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. In turn, pharmacologic inhibition of TGF-β restores expression of TCA cycle enzyme expression and suppresses tumor growth in an orthotopic model of RCC. Taken together, our findings reveal a novel role for the TGF-β /HDAC7 axis in global suppression of TCA cycle enzymes in RCC and provide novel insight into the molecular basis of altered mitochondrial metabolism in this malignancy.Competing Interest StatementThe authors have declared no competing interest.