scholarly journals A Positive Feedback Loop Between c-Myc Upregulation, Glycolytic Shift, and Histone Acetylation Enhances Cancer Stem Cell-like Property and Tumorigenicity of Cr(VI)-transformed Cells

2020 ◽  
Vol 177 (1) ◽  
pp. 71-83
Author(s):  
Marco Clementino ◽  
Jie Xie ◽  
Ping Yang ◽  
Yunfei Li ◽  
Hsuan-Pei Lin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Stem Cell ◽  
Histone Acetylation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cell Transformation ◽  
Transformed Cells ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Positive Feedback Loop

Abstract Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure upregulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the upregulation of c-Myc. The glycolytic shift in Cr(VI)-transformed cells led to increased production of acetyl coenzyme A (acetyl-CoA) and elevation of histone acetylation. This, in turn, upregulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase and c-Myc, forming a positive feedback loop between the upregulation of c-Myc expression, glycolytic shift and increased histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.

scholarly journals SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop

Gut ◽  
2017 ◽  
Vol 66 (12) ◽  
pp. 2149-2159 ◽  
Author(s):  
Chun-Ping Cui ◽  
Carmen Chak-Lui Wong ◽  
Alan Ka-Lun Kai ◽  
Daniel Wai-Hung Ho ◽  
Eunice Yuen-Ting Lau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Mrna Level ◽  
Cancer Stemness ◽  
Positive Feedback Loop ◽  
Sumo Proteases ◽  
Immunocompromised Mice ◽  
Element Sequence

ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.ResultsWe showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.ConclusionsTaken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.

scholarly journals ROS amplification drives mouse spermatogonial stem cell self-renewal

2019 ◽  
Vol 2 (2) ◽  
pp. e201900374 ◽  
Author(s):  
Hiroko Morimoto ◽  
Mito Kanastu-Shinohara ◽  
Narumi Ogonuki ◽  
Satoshi Kamimura ◽  
Atsuo Ogura ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Nuclear Translocation ◽  
Cell Types ◽  
Spermatogonial Stem Cell ◽  
Self Renewal ◽  
Positive Feedback Loop ◽  
Chemical Screening

Reactive oxygen species (ROS) play critical roles in self-renewal division for various stem cell types. However, it remains unclear how ROS signals are integrated with self-renewal machinery. Here, we report that the MAPK14/MAPK7/BCL6B pathway creates a positive feedback loop to drive spermatogonial stem cell (SSC) self-renewal via ROS amplification. The activation of MAPK14 induced MAPK7 phosphorylation in cultured SSCs, and targeted deletion of Mapk14 or Mapk7 resulted in significant SSC deficiency after spermatogonial transplantation. The activation of this signaling pathway not only induced Nox1 but also increased ROS levels. Chemical screening of MAPK7 targets revealed many ROS-dependent spermatogonial transcription factors, of which BCL6B was found to initiate ROS production by increasing Nox1 expression via ETV5-induced nuclear translocation. Because hydrogen peroxide or Nox1 transfection also induced BCL6B nuclear translocation, our results suggest that BCL6B initiates and amplifies ROS signals to activate ROS-dependent spermatogonial transcription factors by forming a positive feedback loop.

scholarly journals Oxidized ATM promotes breast cancer stem cell enrichment through energy metabolism reprogram-mediated acetyl-CoA accumulation

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Dan Yang ◽  
Meixi Peng ◽  
Yixuan Hou ◽  
Yilu Qin ◽  
Xueying Wan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Energy Metabolism ◽  
Cancer Stem Cell ◽  
Tumor Hypoxia ◽  
Tca Cycle ◽  
Glycolytic Flux ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Mammosphere Formation

Abstract Cancer stem cell (CSC) is a challenge in the therapy of triple-negative breast cancer (TNBC). Intratumoral hypoxia is a common feature of solid tumor. Hypoxia may contribute to the maintenance of CSC, resulting in a poor efficacy of traditional treatment and recurrence of TNBC cases. However, the underlying molecular mechanism involved in hypoxia-induced CSC stemness maintenance remains unclear. Here, we report that hypoxia stimulated DNA double-strand breaks independent of ATM kinase activation (called oxidized ATM in this paper) play a crucial role in TNBC mammosphere formation and stemness maintenance by governing a specific energy metabolism reprogramming (EMR). Oxidized ATM up-regulates GLUT1, PKM2, and PDHa expressions to enhance the uptake of glucose and production of pyruvate rather than lactate products, which facilitates glycolytic flux to mitochondrial pyruvate and citrate, thus resulting in accumulation of cytoplasmic acetyl-CoA instead of the tricarboxylic acid (TCA) cycle by regulating ATP-citrate lyase (ACLY) activity. Our findings unravel a novel model of TNBC-CSC glucose metabolism and its functional role in maintenance of hypoxic TNBC-CSC stemness. This work may help us to develop new therapeutic strategies for TNBC treatment.

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