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Energy stress-induced linc01564 activates the serine synthesis pathway and facilitates hepatocellular carcinogenesis

Abstract

Cancer cells undergo metabolic adaption to sustain their survival and growth under metabolic stress conditions, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs contribute to this metabolic adaption of cancer cells. Here we show that linc01564 is induced in response to glucose deprivation by the transcription factor ATF4. Linc01564 functions to facilitate hepatocellular carcinoma cell survival under glucose deprivation by activating the serine synthesis pathway. Mechanistically, linc01564 acts as a competing endogenous RNA for miR-107/103a-3p and attenuates the inhibitory effect of miR-107/103a-3p on PHGDH, the rate-limiting enzyme of the serine synthesis pathway, thereafter leading to increased PHGDH expression. Furthermore, linc01564 is able to promote hepatocellular carcinogenesis via PHGDH. Together, these findings suggest that linc01564 is an important player in the regulation of metabolic adaption of cancer cells and also implicate linc01564 as a potential therapeutic target for cancer.

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Fig. 1: Linc01564 facilitates cancer cell survival under glucose deprivation.
Fig. 2: Linc01564 is a direct transcriptional target of ATF4.
Fig. 3: Linc01564 activates the serine synthesis pathway by increasing PHGDH expression.
Fig. 4: Linc01564 increases PHGDH expression by acting as a molecular sponge for miR107/103a-3p.
Fig. 5: Linc01564 promotes hepatocellular carcinoma cell survival via the miR-107/103a-3p-PHGDH axis.
Fig. 6: Linc01564 functions as an oncogenic long non-coding RNA.

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Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (2019YFA0802600), National Natural Science Foundation of China (91957108, 31671487, and 31871440), Collaborative Innovation Programs of Hefei Science Center, CAS (2019HSC-CIP010), and the Fundamental Research Funds For Central Universities (WK9110000007 and YD2070002007).

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GZ, YY, and YM conceived and designed the project. GZ, YY, HH, KL, YZ, and ZW performed all the experiments and analyzed the data. QW provided the reagents and technical help. YM wrote the manuscript with the help of GZ and YY All authors discussed the results and commented on the manuscript.

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Correspondence to Yide Mei.

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Zhang, G., Yang, Y., Hu, H. et al. Energy stress-induced linc01564 activates the serine synthesis pathway and facilitates hepatocellular carcinogenesis. Oncogene 40, 2936–2951 (2021). https://doi.org/10.1038/s41388-021-01749-x

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