The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer

Yang An Wen, Xiaopeng Xiong, Timothy Scott, Austin T. Li, Chi Wang, Heidi L. Weiss, Li Tan, Emily Bradford, Teresa W.M. Fan, Navdeep Chandel, Terrence A. Barrett, Tianyan Gao*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1955-1969
Number of pages15
JournalCell Death and Differentiation
Volume26
Issue number10
DOIs
StateAccepted/In press - Jan 1 2019

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Colonic Neoplasms
Carcinogenesis
Hypoxia-Inducible Factor 1
Glycolysis
Catenins
Neoplasms
Mitochondrial DNA
Respiration
Up-Regulation
Prolyl Hydroxylases
Gene Expression
Neoplastic Stem Cells
DNA Replication
Mitochondria
Transcription Factors
Adenosine Triphosphate
Glucose
Growth
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Wen, Y. A., Xiong, X., Scott, T., Li, A. T., Wang, C., Weiss, H. L., ... Gao, T. (Accepted/In press). The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer. Cell Death and Differentiation, 26(10), 1955-1969. https://doi.org/10.1038/s41418-018-0265-6
Wen, Yang An ; Xiong, Xiaopeng ; Scott, Timothy ; Li, Austin T. ; Wang, Chi ; Weiss, Heidi L. ; Tan, Li ; Bradford, Emily ; Fan, Teresa W.M. ; Chandel, Navdeep ; Barrett, Terrence A. ; Gao, Tianyan. / The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer. In: Cell Death and Differentiation. 2019 ; Vol. 26, No. 10. pp. 1955-1969.
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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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Wen, YA, Xiong, X, Scott, T, Li, AT, Wang, C, Weiss, HL, Tan, L, Bradford, E, Fan, TWM, Chandel, N, Barrett, TA & Gao, T 2019, 'The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer', Cell Death and Differentiation, vol. 26, no. 10, pp. 1955-1969. https://doi.org/10.1038/s41418-018-0265-6

The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer. / Wen, Yang An; Xiong, Xiaopeng; Scott, Timothy; Li, Austin T.; Wang, Chi; Weiss, Heidi L.; Tan, Li; Bradford, Emily; Fan, Teresa W.M.; Chandel, Navdeep; Barrett, Terrence A.; Gao, Tianyan.

In: Cell Death and Differentiation, Vol. 26, No. 10, 01.10.2019, p. 1955-1969.

Research output: Contribution to journalArticle

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T1 - The mitochondrial retrograde signaling regulates Wnt signaling to promote tumorigenesis in colon cancer

AU - Wen, Yang An

AU - Xiong, Xiaopeng

AU - Scott, Timothy

AU - Li, Austin T.

AU - Wang, Chi

AU - Weiss, Heidi L.

AU - Tan, Li

AU - Bradford, Emily

AU - Fan, Teresa W.M.

AU - Chandel, Navdeep

AU - Barrett, Terrence A.

AU - Gao, Tianyan

PY - 2019/1/1

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N2 - 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.

AB - 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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