Abstract
BEST4 is a member of the bestrophin protein family that plays a critical role in human intestinal epithelial cells. However, its role and mechanism in colorectal cancer (CRC) remain largely elusive. Here, we investigated the role and clinical significance of BEST4 in CRC. Our results demonstrate that BEST4 expression is upregulated in clinical CRC samples and its high-level expression correlates with advanced TNM (tumor, lymph nodes, distant metastasis) stage, LNM (lymph node metastasis), and poor survival. Functional studies revealed that ectopic expression of BEST4 promoted CRC cell proliferation and metastasis, whereas the depletion of BEST4 had the opposite effect both in vitro and in vivo. Mechanistically, BEST4 binds to the p85α regulatory subunit of phosphatidylinositol-3-kinase (PI3K) and promotes p110 kinase activity; this leads to activation of Akt signaling and expression of MYC and CCND1, which are critical regulators of cell proliferation and metastasis. In clinical samples, the expression of BEST4 is positively associated with the expression of phosphorylated Akt, MYC and CCND1. Pharmacological inhibition of Akt activity markedly repressed BEST4-mediated Akt signaling and proliferation and metastasis of CRC cells. Importantly, the interaction between BEST4 and p85α was also enhanced by epidermal growth factor (EGF) in CRC cells. Therapeutically, BEST4 suppression effectively sensitized CRC cells to gefitinib treatment in vivo. Taken together, our findings indicate the oncogenic potential of BEST4 in colorectal carcinogenesis and metastasis by modulating BEST4/PI3K/Akt signaling, highlighting a potential strategy for CRC therapy.
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Acknowledgements
This work was supported by the Natural Science Foundation of Jiangsu Province (BK20190042, BK20181434, and BK20190182), National Natural Science Foundation of China (82022050, 81972601, and 81772541), and the Science and Technology Foundation of Suzhou (SYS2019034, SKJY2021070). This work was also supported by the Fujian Provincial Key Laboratory of Innovative Drug Target Research, the Tang Scholar Funds, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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XH and HW contributed to the study conception and design. XH, WY, YY, RZ, and YZ performed the experiments. XY performed the bioinformatics analysis. FL, JW, XD, HB, and WG collected and evaluated the clinical samples. YZ and LG provided technical support. XH, XY, and HW wrote the manuscript. HW supervised the study.
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He, XS., Ye, WL., Zhang, YJ. et al. Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling. Oncogene 41, 1166–1177 (2022). https://doi.org/10.1038/s41388-021-02160-2
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DOI: https://doi.org/10.1038/s41388-021-02160-2
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