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The TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer
Hyeyoung Nam, … , Sooryanarayana Varambally, Sunil Sudarshan
Hyeyoung Nam, … , Sooryanarayana Varambally, Sunil Sudarshan
Published October 5, 2021
Citation Information: JCI Insight. 2021;6(22):e148438. https://doi.org/10.1172/jci.insight.148438.
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Research Article Cell biology

The TGF-β/HDAC7 axis suppresses TCA cycle metabolism in renal cancer

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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.

Authors

Hyeyoung Nam, Anirban Kundu, Suman Karki, Garrett J. Brinkley, Darshan S. Chandrashekar, Richard L. Kirkman, Juan Liu, Maria V. Liberti, Jason W. Locasale, Tanecia Mitchell, Sooryanarayana Varambally, Sunil Sudarshan

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Figure 3

PGC-1α reexpression upregulates the expression of TCA cycle enzymes and glucose flux to TCA cycle enzymes.

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PGC-1α reexpression upregulates the expression of TCA cycle enzymes and ...
(A) Relative mRNA expression of the indicated genes in a panel of RCC cells relative to normal kidney (n = 3). Transcript levels were normalized to those of TBP (*P < 0.05, **P < 0.01, 1-way ANOVA with Tukey’s multiple-comparison test). (B) Western blot analysis of the indicated proteins in RCC cells stably expressing EV or PGC-1α. Relative intensities for target protein were quantified using ImageJ software. (C) mRNA expression of TCA cycle enzymes from RCC cells transduced either EV or PGC-1α (n = 3). Data represent mean ± SEM (**P < 0.01, 2-tailed Student’s t test). Data are representative of 3 independent experiments. (D) Western blot analysis of the indicated proteins in 769-P cells stably expressing shRNA control (SCR) or 3 independent PGC-1α shRNA constructs. Arrow represents nonspecific band. (E and F) SN12PM6-1 cells stably expressing EV or PGC-1α were orthotopically implanted into the left kidney of SCID mice. At 6 weeks from tumor challenge, kidney tissues were harvested and analyzed for the expression of mRNA (E) and protein for the indicated genes (F) (n = 7). (G) CAKI-1 cells stably expressing EV or PGC-1α were measured for the amount of mtDNA D-Loop structure and MT-CO2 gene (n = 2). (H and I) CAKI-1 cells stably expressing with EV or PGC-1α were incubated with uniformly labeled [U-13C6] glucose for 24 hours. The relative levels of total unlabeled metabolites (H) and labeled TCA cycle intermediates (I) (M+2) were analyzed using LC-MS (*P < 0.05, **P < 0.01, 2-tailed Student’s t test).

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