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

Zhi Miao; Xiaomeng Zhao; Xiang Liu

doi:10.1016/j.yexcr.2022.113439

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

Exp Cell Res. 2023 Jan 1;422(1):113439. doi: 10.1016/j.yexcr.2022.113439. Epub 2022 Dec 1.

Authors

Zhi Miao¹, Xiaomeng Zhao², Xiang Liu³

Affiliations

¹ Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, 300072, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China. Electronic address: 18622901209@163.com.
² Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, 300072, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.
³ Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430016, China; The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.

PMID: 36464122
DOI: 10.1016/j.yexcr.2022.113439

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.

Keywords: Colorectal cancer; Hypoxia; Lactylation; Stemness; β-catenin.

MeSH terms

Cell Line, Tumor
Cell Movement
Cell Proliferation
Colorectal Neoplasms* / pathology
Gene Expression Regulation, Neoplastic
Humans
Hypoxia
Tumor Microenvironment
Wnt Signaling Pathway
beta Catenin* / genetics
beta Catenin* / metabolism

Substances

beta Catenin