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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 1

Suppression of TCA cycle enzymes in ccRCC.

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Suppression of TCA cycle enzymes in ccRCC.
(A) Immunoblot analysis of AC...
(A) Immunoblot analysis of ACO2 and SUCLG1 in patient-matched normal kidney (N) and tumor (T) (n = 6). (B) Western blot analysis of ACO2 and SUCLG1 in a panel of RCC cell lines relative to RPTEC primary renal proximal tubule epithelial cells. The band intensities for ACO2 and SUCLG1 protein levels were quantified with reference to actin control bands using ImageJ program (NIH). (C) Protein expression of ACO2 and SUCLG1 across cancer subtypes from the CPTAC cohorts. (D) Heatmap representing expression patterns of TCA cycle enzymes in normal kidney (n = 72), VHL mutant RCC (n = 224), and VHL WT RCC (n = 225). Data were extracted from TCGA KIRC data set. The heatmap shows the log10-transformed TPM values for each gene. (E) Heatmap representing expression patterns of TCA cycle enzymes using the Illumina Human HT-12 v4 bead array in the 3-patient groups (normal, n = 9; primary, n = 9; and metastasis, n = 26). Colors in the heatmap represent log-transformed quantile normalized expression values. (F) Relative mRNA expression of TCA cycle enzymes in a separate cohort of patient-matched samples. Transcript levels were normalized to those of TBP (n = 4–6). Asterisks indicate significant differences compared with normal kidney (*P < 0.05, ** P < 0.01, 1-way ANOVA with Tukey’s multiple-comparison test).

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