Superenhancers activate the autophagy-related genes Beclin1 and LC3B to drive metastasis and drug resistance in osteosarcoma

Abstract

Metastasis and drug resistance are the leading causes of poor prognosis in patients with osteosarcoma. Identifying the relevant factors that drive metastasis and drug resistance is the key to improving the therapeutic outcome of osteosarcoma. Here, we reported that autophagy was highly activated in metastatic osteosarcoma. We found increased autophagolysosomes in metastatic osteosarcoma cell lines by using electron microscopy, Western blot, and immunofluorescence experiments. We further examined the expression of the autophagy-related genes Beclin1 and LC3B in 82 patients through immunohistochemistry and found that Beclin1 and LC3B were highly related to unfavorable prognosis of osteosarcoma. Knockdown of Beclin1 and LC3B reduced invasion, metastasis, and proliferation in metastatic osteosarcoma cells. In vitro and in vivo studies also demonstrated that inhibiting by 3-MA inhibited cell growth and metastasis. Moreover, we demonstrated that autophagy-related genes were activated by SEs and that the inhibition of SEs by JQ-1 decreased the metastasis of osteosarcoma. Overall, our findings highlighted the association of autophagy with osteosarcoma progression and shed new light on autophagy-targeting therapy for osteosarcoma.

Keywords

osteosarcoma / autophagy / metastasis / drug resistance / Beclin1 / LC3B

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81602069). We thank the National Research Center for Translational Medicine (Shanghai) for supporting this study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0919-0 and is accessible for authorized users.

Compliance with ethics guidelines

Hongyi Wang, Zhuochao Liu, Jun Wang, Fangqiong Hu, Qi Zhou, Li Wei, Qiyuan Bao, Jizhuang Wang, Jing Liang, Zhihong Liu, and Weibin Zhang declare that they have no conflicts of interest. This study was approved by the Ethics Committee of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and conducted according to the Declaration of Helsinki and its amendments. Informed consent was acquired.

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