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FOXA2 inhibits doxorubicin-induced apoptosis via transcriptionally activating HBP rate-limiting enzyme GFPT1 in HCC cells

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Abstract

Apoptosis plays an important role in both carcinogenesis and cancer treatment. Understanding the mechanisms through which resistance to apoptosis occurs in cancer cells has huge implications for cancer treatment. Although pieces of evidence have shown that elevated levels of global O-GlcNAcylation play an anti-apoptotic role in myriad cancers, the underlying mechanism is still ambiguous. In this study, we demonstrated that FOXA2, an essential transcription factor for liver homeostasis and hepatocellular carcinoma (HCC) development, inhibits doxorubicin (DOX)-induced apoptosis through elevating cellular O-GlcNAcylation in HCC cells. In response to DOX treatment, elevated FOXA2 and global O-GlcNAcylation level was observed in HCC cells, and higher FOXA2 levels indicated lower levels of DOX-induced apoptosis. Subsequently, we demonstrated that FOXA2 is a direct transcriptional activator of the hexosamine biosynthetic pathway (HBP) rate-limiting enzyme GFPT1. The upregulation of FOXA2 expression induced the synthesis of intracellular UDP-GlcNAc, which is the sugar substrate of O-GlcNAcylation produced by the HBP. The flux through the HBP elevated the global O-GlcNAcylation level and led to the activation of survival signaling pathways in HCC cells. Furthermore, GFPT1 was proved to be an important downstream regulator of FOXA2-mediated apoptotic suppression. These results provide insights into the molecular mechanism by which FOXA2 inhibits DOX-induced HCC cell apoptosis and suggest that targeting FOXA2 might offer a new strategy for HCC treatment.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the Natural Science Foundation of China (31870793, 31971214), Natural Science Foundation of Liaoning Province (2019-MS-042), and the Fundamental Research Funds for the Central Universities (DUT20YG130, DUT20YG116).

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Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China

    Huang Huang, Yuhan Wang, Tianmiao Huang, Lingyan Wang, Yangzhi Liu, Qiong Wu, Ang Yu, Meiyun Shi, Xiaoyu Wang, Wenli Li, Jianing Zhang & Yubo Liu

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  1. Huang Huang
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Contributions

Huang H conceived and designed the study. Huang H, Wang Y, Huang T, Wang L, Liu Yangzhi, Wu Q, Yu A, Shi M, and Wang X performed the experiments. Huang H and Liu Yubo wrote the paper. Li W and Zhang J reviewed and edited the manuscript. All authors read and approved the manuscript. The authors declared that all data were generated in-house and that no paper mill was used.

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Correspondence to Jianing Zhang or Yubo Liu.

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Key Points FOXA2 is a direct transcriptional activator of the HBP rate-limiting enzyme GFPT1. FOXA2 promotes the synthesis of UDP-GlcNAc and thus elevates cellular O-GlcNAcylation. FOXA2 inhibits DOX-induced apoptosis by elevating O-GlcNAcylation in HCC cells.

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Huang, H., Wang, Y., Huang, T. et al. FOXA2 inhibits doxorubicin-induced apoptosis via transcriptionally activating HBP rate-limiting enzyme GFPT1 in HCC cells. J Physiol Biochem 77, 625–638 (2021). https://doi.org/10.1007/s13105-021-00829-6

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