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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 8

HDAC7/SMAD complex represses the TCA cycle enzyme expression.

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HDAC7/SMAD complex represses the TCA cycle enzyme expression.
(A) Wester...
(A) Western blot analysis of the indicated protein levels in WT CAKI-1 (WT) and HDAC7 CRISPR–KO CAKI-1 (HDAC7-KO). (B) WT CAKI-1 and HDAC7-KO cells were treated with or without TGF-β (1 ng/mL) for 24 hours, followed by the immunoblot analysis for OGDH. (C) Immunoblot analysis for Myc and HDAC7 in HEK293T cells transfected with EV or Myc-tagged HDAC7 for 48 hours. (D) HEK293T cells transfecting with Myc-tagged HDAC7 were immunoprecipitated using either anti-SMAD4, anti-SMAD2, or control IgG. IP samples with individual SMAD antibody were followed by immunoblotting (IB) for Myc-tagged HDAC7. IgG pulldown is included as a control. (E) ChIP-qPCR was performed on CAKI-1 cells with mouse IgG, anti-HDAC1, and anti-HDAC7. The enriched DNA was quantified by qPCR with primer sets targeting the potential SMAD binding sites upstream of the SUCLG1 transcription start site. Enrichment was calculated with the percent input method (n = 2/group, 3 independent experiments). Asterisks indicate significant differences compared with IgG control. (F) RNA-Seq analysis for HDAC7 mRNA expression in renal tumors from the TCGA data set using UALCAN analysis. (G) Protein expression of HDAC7 in normal kidney and primary tumor from the CPTAC data using UALCAN analysis. (H) Immunoblot analysis of HDAC7 in patient-matched normal kidney (N) and tumor (T). **P < 0.01, 1-way ANOVA with Tukey’s multiple-comparison test.

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