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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 4

The expressions of PPARGC1A and TCA cycle enzymes are restored by blockade of TGF-β signaling.

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The expressions of PPARGC1A and TCA cycle enzymes are restored by blocka...
(A) Relative mRNA expression of PPARGC1A in CAKI-1 cells treated with either DMSO (Con) or indicated pharmacological TGF-β inhibitors (10 μM) for 48 hours (n = 3). (B) Immunoblot analysis for PGC-1α protein expression in nuclear lysate from 769-P cells treated with indicated TGF-β inhibitors for 48 hours. (C and D) Relative mRNA expression of TCA cycle enzymes in 769-P and CAKI-1 cells treated with either DMSO or indicated TGF-β inhibitors (10 μM) for 48 hours (n = 3) (*P < 0.05, **P < 0.01, 1-way ANOVA with Tukey’s multiple-comparison test). (E) Immunoblot analysis for ACO2 and SUCLG1 protein expression in cell lysates from CAKI-1 cells treated with the indicated TGF-β inhibitor for 48 hours. (F) Western blot analysis of PGC-1α in nuclear lysates from HK2 cells exposed to TGF-β (1 ng/mL) for 24 hours. Lamin B1 was used as a loading control. (G) HK2 cells were exposed to TGF-β (1 ng/mL) for 24 hours, followed by immunoblot analysis for OGDH and SUCLG2 expression. Data are representative of 2–3 independent experiments. The unedited versions of all blot images are provided in Supplemental Figure 6.

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