LncRNA LINC00525 activates HIF-1α through miR-338-3p / UBE2Q1 / β-catenin axis to regulate the Warburg effect in colorectal cancer

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ABSTRACT

Warburg effect is considered to be related to the malignancy of tumor cells under hypoxic conditions, but the underlying mechanism remains unknown. In this article, it has been reported that lncRNA LINC00525 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. It was found that LINC00525 was up-regulated, and promoted cell proliferation in colorectal cancer in vitro and in vivo. In colorectal cancer cells, hypoxia increasedLINC00525 expression, whereas knocking down LINC00525 reduced hypoxia-enhanced glycolysis. For specific molecular mechanisms, it was found that LINC00525 promoted UBE2Q1 expression by binding miR-338-3p, and UBE2Q1-stabilized β-catenin enhances hypoxia-enhanced glycolysis by activating HIF-1α. In conclusion, these findings showed that LINC00525 was essential for hypoxia-enhanced glycolysis; its mechanism was related to activating HIF-1α through miR-338-3p/UBE2Q1/β-catenin axis in colorectal cancer cells.

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Understanding the Warburg effect: the metabolic requirements of cell proliferation.

Craig B Thompson, Matthew Vander Heiden, Lewis Cantley (2009)

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

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The Warburg Effect: How Does it Benefit Cancer Cells?

Maria Liberti, Jason Locasale (2016)

Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of completely functioning mitochondria and, together, is known as the 'Warburg Effect'. The Warburg Effect has been documented for over 90 years and extensively studied over the past 10 years, with thousands of papers reporting to have established either its causes or its functions. Despite this intense interest, the function of the Warburg Effect remains unclear. Here, we analyze several proposed explanations for the function of Warburg Effect, emphasize their rationale, and discuss their controversies.

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Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Eva M. Pålsson-McDermott, Anne M Curtis, Gautam Goel … (2015)

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

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Journal

Journal ID (nlm-ta): Bioengineered

Journal ID (iso-abbrev): Bioengineered

Title: Bioengineered

Publisher: Taylor & Francis

ISSN (Print): 2165-5979

ISSN (Electronic): 2165-5987

Publication date (Electronic, pub): 13 February 2022

Publication date (Electronic, collection): 2022

Publication date PMC-release: 13 February 2022

Volume: 13

Issue: 2

Pages: 2552-2565

Affiliations

[a ]Department of Colorecal & Anal Surgery, The First Hospital of JiLin University; Changchun, China

[b ]Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of JiLin University;

Author notes

CONTACT Guangyi Wang guangyi@ 123456jlu.edu.cn Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of JiLin University; , No. 71Xinmin Street, Chaoyang District, Changchun City, Jilin Province 130021, China

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Guangyi Wang https://orcid.org/0000-0002-5737-4420

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Publisher ID: 2018538

DOI: 10.1080/21655979.2021.2018538

PMC ID: 8973709

PubMed ID: 35156520

SO-VID: e9bb7665-3ba5-4f1f-8f95-5ac49b48f1b4

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

LncRNA LINC00525 activates HIF-1α through miR-338-3p / UBE2Q1 / β-catenin axis to regulate the Warburg effect in colorectal cancer

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Most cited references 33

Understanding the Warburg effect: the metabolic requirements of cell proliferation.

The Warburg Effect: How Does it Benefit Cancer Cells?

Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

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