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TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth.

ABSTRACT: Tgif1 (thymine-guanine-interacting factor 1) and Tgif2 repress gene expression by binding directly to DNA or interacting with transforming growth factor (TGF) β-responsive SMADs. Tgifs are essential for embryogenesis and may function in tumor progression. By analyzing both gain and loss of Tgif function in a well-established mouse model of intestinal cancer, we show that Tgifs promote adenoma growth in the context of mutant Apc (adenomatous polyposis coli). Despite the tumor-suppressive role of TGFβ signaling, transcriptome profiling of colon tumors suggests minimal effect of Tgifs on the TGFβ pathway. Instead, it appears that Tgifs, which are up-regulated in Apc mutant colon tumors, contribute to reprogramming metabolic gene expression. Integrating gene expression data from colon tumors with other gene expression and chromatin-binding data identifies a set of direct Tgif target genes encoding proteins involved in acetyl CoA and pyruvate metabolism. Analysis of both tumor and nontumor tissues indicates that these genes are targets of Tgif repression in multiple settings, suggesting that this is a core Tgif function. We propose that Tgifs play an important role in regulating basic energy metabolism in normal cells, and that this function of Tgifs is amplified in some cancers.

SUBMITTER: Shah A

PROVIDER: S-EPMC6446543 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.

Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.

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TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth.

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