SALL4 has recently been identified to promote chemo-resistance in multiple types of cancer, but the underlying mechanism remains to be fully established. Open chromatin structure is important for DNA damage response (DDR) and DNA repair. Here, we demonstrate that SALL4 promotes open chromatin by destabilizing heterochromatin protein 1α (HP1α) by recruiting ubiquitin E3 ligase CUL4B to HP1α. The silencing of SALL4 in cancer cells decreased the expression levels of Glut1 and inhibited glycolysis in cancer cells. The upregulation of HP1α in human cancer cells suppressed open chromatin, glycolysis and Glut1 expression levels. Therefore, SALL4 promotes the expression of Glut1 and open chromatin through a HP1α-dependent mechanism. Impaired DDR in SALL4-deficient human cancer cells can be rescued by the restored expression of Glut1, indicating the importance of HP1α-Glut1 axis in SALL4-mediated DDR. These findings demonstrate that SALL4 could induce drug resistance by enhancing DDR and DNA repair through promoting glycolysis and subsequent chromatin remodeling.
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We thank Michael Qiu for technical support. This study is supported by the National Natural Science Foundation of China (No. 815300045, 81373166, 81430032), a grant from the National High-tech R&D Program (863 Program No. 2015AA020310), Guangdong Provincial Key Laboratory of Tumor Immunotherapy and Guangzhou Key Laboratory of Tumor Immunology Research, South Wisdom Valley Innovative Research Team Program (2014) No. 365, Major basic research developmental project of the Natural Science Foundation of Guangdong Province, Shenzhen Municipal Science and Technology Innovation Council (20140405201035), and grants from California Institute for Regenerative Medicine (TR3-05559, RT3-07899).
J.K. with the help of S.X. and L.Y. performed experiments. J.K, X.F. and Y.X. planned the experiments and interpreted the data. X.F. and Y.X. provided the administrative support. J.K. and Y.X. were responsible for the initial draft of the manuscript, whereas other authors contributed to the final edited versions.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Kim, J., Xu, S., Xiong, L. et al. SALL4 promotes glycolysis and chromatin remodeling via modulating HP1α-Glut1 pathway. Oncogene 36, 6472–6479 (2017). https://doi.org/10.1038/onc.2017.265
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