Abstract
Cancer cells are known to upregulate aerobic glycolysis to promote growth, proliferation, and survival. However, the role of mitochondrial respiration in tumorigenesis remains elusive. Here we report that inhibition of mitochondrial function by silencing TFAM, a key transcription factor essential for mitochondrial DNA (mtDNA) replication and the transcription of mtDNA-encoded genes, markedly reduced tumor-initiating potential of colon cancer cells. Knockdown of TFAM significantly decreased mitochondrial respiration in colon cancer cells; however, the cellular levels of ATP remained largely unchanged as a result of increased glycolysis. This metabolic alteration rendered cancer cells highly susceptible to glucose deprivation. Interestingly, upregulation of glycolysis was independent of hypoxia-inducible factor-1 (HIF1) as TFAM knockdown cells fail to stabilize HIF1α under hypoxic conditions. Moreover, knockdown of TFAM results in decreased expression of genes-associated cancer stem cells downstream of Wnt/β-catenin signaling. Metabolic analysis reveals that the level of α-ketoglutarate (α-KG) was significantly upregulated in TFAM knockout cells. Silencing of prolyl hydroxylase domain-containing protein 2 (PHD2), a α-KG-dependent dioxyenase, rescued the expression of target genes of both HIF1α and Wnt/β-catenin. Furthermore, intestinal-specific knockout of TFAM prevents tumor formation in Apc-mutant mouse models of colon cancer. Taken together, our findings identify a novel role of mitochondria-mediated retrograde signaling in regulating Wnt signaling and tumor initiation in colon cancer.
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Acknowledgements
This work was supported by R01CA133429 (TG), 1U24DK097215 (T.W.-M.F.) and 5R35CA197532 (NSC). The studies were conducted with support provided by the Redox Metabolism, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Cell Sorting, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558) as well as the Center for Environmental and Systems Biochemistry (CESB) at the University of Kentucky.
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Y-AW, TAB, and TG designed all aspects of the study; Y-AW, XX, TS, ATL, CW, HLW, and LT performed experiments and analysis; EB, TWMF, and NSC provided input into the project; Y-AW and TG wrote the manuscript.
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Wen, YA., Xiong, X., Scott, T. et al. The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer. Cell Death Differ 26, 1955–1969 (2019). https://doi.org/10.1038/s41418-018-0265-6
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DOI: https://doi.org/10.1038/s41418-018-0265-6
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