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STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1

Abstract

Chromodomain Y-like 2 (CDYL2), as a member of CDY family known to be involved in spermatogenesis, has been reported to participate in breast cancer development recently, but its exact biological role in hepatocellular carcinoma (HCC) remains unclear. Here, we observed that CDYL2 was down-regulated in human primary HCC tissues and the low levels of CDYL2 expression were correlated with poor survival. Gain- and loss-of-function experiments showed that CDYL2 inhibited the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, CDYL2 down-regulates solute carrier family 7 member 6 (SLC7A6) by decreasing the enrichment of H3K4me3 on the promoter region of SLC7A6. Additionally, we also found that signal transducer and activator of transcription 5A (STAT5A) could directly and positively regulate the expression of CDYL2. Thus, CDYL2 was regulated by STAT5A, and suppressed the amino acid transportation through down-regulation of SLC7A6, and then inhibits the mTORC1/S6K pathway, a master regulator of cell growth. Consistently, CDYL2 expression correlated significantly with STAT5A and SLC7A6 expression in HCC. Collectively, we propose a model for a STAT5A/CDYL2/SLC7A6 axis that provides novel insight into CDYL2, which may serve as a potential factor for predicting prognosis and a therapeutic target for HCC patients.

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Fig. 1: Low expression of CDYL2 and its prognostic significance in HCC.
Fig. 2: CDYL2 inhibits HCC cell proliferation in vitro and in vivo.
Fig. 3: CDYL2 inhibits HCC cell mobility and metastasis in vitro and in vivo.
Fig. 4: STAT5A suppressed HCC progression by inducing CDYL2 expression.
Fig. 5: CDYL2 inhibits HCC progression by suppressing SLC7A6 expression.
Fig. 6: STAT5A down-regulates SLC7A6 by inducing CDYL2 expression.
Fig. 7: Correlation of STAT5A, CDYL2 and SLC7A6 in HCC samples.

Data availability

All datasets on which the conclusions of the paper rely are available to readers.

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Acknowledgements

The authors are grateful to Dr. Daqiang Li for donating pLVX-CDYL2 vector. This work was supported by the National Natural Science Foundation of China [Grant number 82173331, 81972580, 81773152].

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XC, JL performed study, writing and revision of the paper. ZW, XZ helped to perform this study. LZ, LZ, XL provided acquisition, analysis of data. CG performed immunohistochemical. FZ, MY carried out animal experiments. TC, HX, YC provided clinical samples. HT, HL, JL provided technical support. JL supervised this study. All authors read and approved the final paper.

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Correspondence to Jinjun Li.

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Chen, X., Wang, Z., Zhao, X. et al. STAT5A modulates CDYL2/SLC7A6 pathway to inhibit the proliferation and invasion of hepatocellular carcinoma by targeting to mTORC1. Oncogene 41, 2492–2504 (2022). https://doi.org/10.1038/s41388-022-02273-2

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