HMGCS2 enhances invasion and metastasis via direct interaction with PPARα to activate Src signaling in colorectal cancer and oral cancer

Chen, Shih-Wen; Chou, Chiang-Ting; Chang, Cheng-Chi; Li, Yue-Ju; Chen, Szu-Ta; Lin, Iuon-Chang; Kok, Sang‐Heng; Cheng, Shih‐Jung; Lee, Jang‐Jaer; Wu, Tso-Ren; Kuo, Min-Liang; Lin, Bi‐Fong

doi:10.18632/oncotarget.13006

Cited by 60 publications

(54 citation statements)

References 30 publications

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“…Excluding gut epithelial cells and hepatocytes, HMGCS2 is nearly absent in almost all other mammalian cells, but the prospect of extrahepatic ketogenesis has been raised in tumor cells, astrocytes of the central nervous system, the kidney, pancreatic β cells, retinal pigment epithelium (RPE), and even in skeletal muscle (Adijanto et al, 2014; Avogaro et al, 1992; El Azzouny et al, 2016; Grabacka et al, 2016; Kang et al, 2015; Le Foll et al, 2014; Nonaka et al, 2016; Takagi et al, 2016a; Thevenet et al, 2016; Zhang et al, 2011). Ectopic HMGCS2 has been observed in tissues that lack net ketogenic capacity (Cook et al, 2016; Wentz et al, 2010), and HMGCS2 exhibits prospective ketogenesis-independent ‘moonlighting’ activities, including within the cell nucleus (Chen et al, 2016; Kostiuk et al, 2010; Meertens et al, 1998). …”

Section: Controversies In Extrahepatic Ketogenesismentioning

confidence: 99%

“…Alternatively, tumor cell ketogenesis has also been proposed. Dynamic shifts in ketogenic gene expression are exhibited during cancerous transformation of colonic epithelium, a cell type that normally expresses HMGCS2, and a recent report suggested that HMGCS2 may be a prognostic marker of poor prognosis in colorectal and squamous cell carcinomas (Camarero et al, 2006; Chen et al, 2016). Whether this association requires or involves ketogenesis, or a moonlighting function of HMGCS2, remains to be determined.…”

Section: Ketone Bodies In Cancer Biologymentioning

confidence: 99%

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Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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Section: Controversies In Extrahepatic Ketogenesismentioning

confidence: 99%

Section: Ketone Bodies In Cancer Biologymentioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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“…The HLD-specific deletion enhancer, SFA1 , has seven human homologs, of which three ( ADH4, ADH1A , and ADH6 ) were UES in gCSI data ( Additional File 1, Figure S7) ‥ High expression of ADH1A or ADH6 was predictive of improved prognosis for pancreatic adenocarcinoma [185] and high expression of ADH1A or ADH4 had improved prognosis for non-small cell lung cancer [186]. The ERG13 homolog, GCS1 , has been suggested as a synthetic lethal target for BRAF V600E -positive human cancers [187], and HMGCS2 plays a role in invasion and metastasis in colorectal and oral cancer [188]. Thus, doxorubicin treatment may have anti-tumor efficacy specifically in glycolytic tumors with reduced expression of SFA1 and ERG13 homologs.…”

Section: Resultsmentioning

confidence: 99%

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Santos

Hartman

2019

Preprint

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Background: Saccharomyces cerevisiae represses respiration in the presence of adequate glucose, mimicking the Warburg effect, termed aerobic glycolysis. We conducted yeast phenomic experiments to characterize differential doxorubicin-gene interaction, in the context of respiration vs. glycolysis. The resulting systems level biology about doxorubicin cytotoxicity, including the influence of the Warburg effect, was integrated with cancer pharmacogenomics data to identify potentially causal correlations between differential gene expression and anti-cancer efficacy. Methods: Quantitative high-throughput cell array phenotyping (Q-HTCP) was used to measure cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library, treated with escalating doxorubicin concentrations in fermentable and non-fermentable media. Doxorubicin-gene interaction was quantified by departure of the observed and expected phenotypes for the doxorubicin-treated mutant strain, with respect to phenotypes for the untreated mutant strain and both the treated and untreated reference strain. Recursive expectation-maximization clustering (REMc) and Gene Ontology-based analyses of interactions were used to identify functional biological modules that buffer doxorubicin cytotoxicity, and to characterize their Warburg-dependence. Yeast phenomic data was applied to cancer cell line pharmacogenomics data to predict differential gene expression that causally influences the anti-tumor efficacy, and potentially the anthracycline-associated host toxicity, of doxorubicin. Results: Doxorubicin cytotoxicity was greater with respiration, suggesting the Warburg effect can influence therapeutic efficacy. Accordingly, doxorubicin drug-gene interaction was more extensive with respiration, including increased buffering by cellular processes related to chromatin organization, protein folding and modification, translation reinitiation, spermine metabolism, and fatty acid beta-oxidation. Pathway enrichment was less notable for glycolysis-specific buffering. Cellular processes exerting influence relatively independently, with respect to Warburg status, included homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, and actin cortical patch localization. Causality for differential gene expression associated with doxorubicin cytotoxicity in tumor cells was predicted within the biological context of the phenomic model. Conclusions: Warburg status influences the genetic requirements to buffer doxorubicin toxicity. Yeast phenomics provides an experimental platform to model the complexity of gene interaction networks that influence human disease phenotypes, as in this example of chemotherapy response. High-resolution, systems level yeast phenotyping is useful to predict the biological influence of functional variation on disease, offering the potential to fundamentally advance precision medicine.

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“…Some studies have shown that HMGCS2 may relate to the progression of cancer and play a key role in enhancing the phenotype of tumor migration, invasion, and metastasis through an independent metabolic mechanism in vitro. HMGCS2 can also increase the heterotopic expression of cancer cells to enhance the vitality of cancer cells (Chen et al, ). Intestinal fatty acid binding protein 2 ( FABP2 ) is an intracellular protein, a highly specific marker of intestinal necrosis, expressed in intestinal epithelial cells and combined with saturated and unsaturated long‐chain fatty acids to participate in the absorption and transport of dietary fatty acids (Alharbi et al, ; Kano, Takahashi, Inoue, Tanaka, & Okita, ; Khattab, Abo‐Elmatty, Ghattas, Mesbah, & Mehanna, ).…”

Section: Discussionmentioning

confidence: 99%

Alternating consumption of β‐glucan and quercetin reduces mortality in mice with colorectal cancer

et al. 2019

Food Science & Nutrition

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The current dietary recommendations for disease prevention and management are scarce and are not well supported. Beta‐glucan or quercetin in a diet can alleviate colorectal cancer (CRC) by regulating the gut microbiota and related genes, but the effects of alternating their consumption for routine ingestion during CRC occurrence remain unknown. This study investigated the effects of alternating the consumption of β‐glucan and quercetin for routine ingestion on CRC development in mice. The mortality rate, colonic length, inflammatory cytokines, gut microbiota, and colonic epithelial gene expression in healthy and CRC mice that consumed normal and alternate diets were compared and studied. The results showed that alternating the consumption of β‐glucan and quercetin (alternating among a β‐glucan diet, a normal diet and a normal diet that was supplemented with quercetin) alleviated colon damage and reduced the mortality rate in CRC mice, with a reduction in mortality of 12.5%. Alternating the consumption of β‐glucan and quercetin significantly decreased the TNF‐α level, increased the relative abundance of Parabacteroides, and downregulated three genes (Hmgcs2, Fabp2, and Gpt) that are associated with inflammation and cancer. Alternating the consumption of some bioactive compounds, such as β‐glucan and quercetin, in food can contribute to human health. This experiment provided some experimental evidence for the dietary recommendations for disease prevention and management.

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HMGCS2 enhances invasion and metastasis via direct interaction with PPARα to activate Src signaling in colorectal cancer and oral cancer

Cited by 60 publications

References 30 publications

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

Alternating consumption of β‐glucan and quercetin reduces mortality in mice with colorectal cancer

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