Hypoxia induced β-catenin lactylation promotes the cell proliferation and stemness of colorectal cancer through the wnt signaling pathway

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Abstract

Colorectal cancer (CRC) is a common malignant tumor of digestive system. Its incidence rate and mortality rate ranks the third among all the malignant tumors. The objective of this study was to explore the role of β-catenin in the CRC progression. The CRC tissues were collected to analyze the β-catenin levels. The CRC cells (SW620 and RRKO) were treated with hypoxia to simulate the hypoxic microenvironment of tumor in vitro. The β-catenin levels in the CRC cells were assessed with RT-qPCR, Western blot and Immunofluorescence. The cell biological behaviors were determined with CCK-8, flow cytometry and sphere formation assays. Besides, the glucose uptake, lactate production, ECAR and OCR was detected by seahorse. For the β-catenin lactylation determination, the IP and Western blot assay was performed. Then the protein stability of β-catenin was measured after cycloheximide treatment. The results showed that β-catenin was highly expressed in the CRC tissues and cells. Hypoxia treatment dramatically increased the protein levels and lactylation of β-catenin in the CRC cells. In addition, β-catenin knockdown dramatically inhibited the cell growth and stemness of the CRC cells. Besides, activation of Wnt signaling pathway neutralized the role of sh-β-catenin in the hypoxia treated CRC cells. In conclusion, this study confirmed that hypoxia induced the glycolysis promoted the β-catenin lactylation, which further enhanced the protein stability and expression of β-catenin, thus aggravating the malignant behaviors of CRC cells.

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On the Origin of Cancer Cells

O WARBURG (1956)

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Xinming Jing, Fengming Yang, Chuchu Shao … (2019)

Aim Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. Methods Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms. Results Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. Conclusion Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.