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This research aims to clarify the role of ST3GAL1 in colorectal cancer metastasis and the underlying mechanisms involved.

March 31, 2026Journal of Translational Medicine0 citationsOpen Access

ST3GAL1 drives colorectal cancer metastasis by mediating NRF2-induced activation of the integrin-α6β4 signaling pathway via sialylation modification

YYYang YangCentral South University of Forestry and Technology SBSimeng BaoLiaoning University QXQingyang XingChina Medical University

Key Points

This research aims to clarify the role of ST3GAL1 in colorectal cancer metastasis and the underlying mechanisms involved.
Used dual luciferase mutation experiments and ChIP-qPCR to validate ST3GAL1 transcription regulation by NRF2.
Assessed ST3GAL1 expression in CRC tissues via western blot and immunohistochemistry.
Performed functional assays including CCK-8, Transwell, and flow cytometry to evaluate tumor cell behavior.
Conducted in vivo experiments using various xenograft models to study tumor growth and chemotherapy response.
Identified sialylation sites on integrin-α6β4 through lectin affinity immunoprecipitation and site-directed mutagenesis.
ST3GAL1 was found to be highly expressed in CRC clinical samples, correlating with poor patient prognosis.
Down-regulation of ST3GAL1 resulted in reduced CRC cell proliferation and metastasis, and improved sensitivity to chemotherapy.
Overexpression of wild-type ST3GAL1 promoted malignancy, while the catalytic domain mutant showed no effect.
ST3GAL1 mediates the sialylation of integrin-α6β4, activating the FAK/SRC signaling pathway, promoting CRC progression.

Abstract

Colorectal cancer (CRC) is one of the most lethal malignancies. ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3GAL1) is a glycosyltransferase that catalyzes the transfer of sialic acid to Galβ1-3-GalNAc-Ser/Thr in an α2,3-linked manner. This study aimed to investigate the function of ST3GAL1 in CRC and reveal its potential mechanism. The transcriptional regulation of ST3GAL1 by Nrf2 was validated using dual luciferase mutation experiments and ChIP-qPCR. The expression of ST3GAL1 in CRC tissues was assessed using western blot and immunohistochemistry. Functional experiments including CCK-8, Transwell and flow cytometry were conducted to evaluate the malignant behavior of tumor cells. In vivo tumor growth, metastasis, and chemotherapy response were assessed using subcutaneous, splenic injection, and intrarectal xenograft models. Lectin affinity immunoprecipitation and site-directed mutagenesis were used to identify sialylation sites on integrin-α6β4. We first identified that NRF2 directly binds to two key regions on the promoter of ST3GAL1 (-1107~-771 and − 437 ~ + 195) to enhance the transcriptional activity of ST3GAL1. Subsequently, ST3GAL1 was proved to be abnormally highly expressed in CRC clinical samples and serves as a prognostic marker for poor prognosis of patients. Next, we confirmed that down-regulation of ST3GAL1 suppressed the proliferation and metastasis of CRC cells in vitro and in vivo, and also enhanced the sensitivity to 5-fluorouracil chemotherapy. Moreover, overexpression of the wild-type ST3GAL1 (ST3GAL1-WT) promotes the malignant phenotype of CRC, whereas the catalytic domain-mutated vector (ST3GAL1-H299A) has no effects, indicating that the tumor-promoting function of ST3GAL1 is dependent on its sialyltransferase activity. Mechanistically, the lectin affinity immunoprecipitation and site-directed mutagenesis revealed that ST3GAL1 mediates sialylation of integrin-α6β4 at specific O-glycosylation sites (ITGA6: S934, S937, T944; ITGB4: S1515, S1517, T1524), thereby activating the downstream FAK/SRC signaling pathway. This study uncovers a novel Nrf2-ST3GAL1-integrin-α6β4/FAK/SRC regulatory axis driven by sialylation modification, which promotes CRC progression. ST3GAL1 represents a potential therapeutic target for CRC, providing a new strategy for treating metastatic and chemotherapy-resistant CRC.

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