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

doi:10.1007/s11684-022-0919-0

Front. Med.

2022, Vol. 16

Issue (6) : 883-895 https://doi.org/10.1007/s11684-022-0919-0

RESEARCH ARTICLE

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

Hongyi Wang^1,², Zhuochao Liu¹, Jun Wang², Fangqiong Hu², Qi Zhou², Li Wei², Qiyuan Bao¹, Jizhuang Wang², Jing Liang², Zhihong Liu^1,²(

), Weibin Zhang¹(

)

¹. Department of Orthopedics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². Shanghai Institute of Traumatology and Orthopedics, Shanghai 200025, China

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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

Corresponding Author(s): Zhihong Liu,Weibin Zhang

Just Accepted Date: 23 August 2022 Online First Date: 03 November 2022 Issue Date: 16 January 2023

Cite this article:

Hongyi Wang,Zhuochao Liu,Jun Wang, et al. Superenhancers activate the autophagy-related genes Beclin1 and LC3B to drive metastasis and drug resistance in osteosarcoma[J]. Front. Med., 2022, 16(6): 883-895.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0919-0
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I6/883

Fig.1 Autophagic flux in metastatic and nonmetastatic osteosarcoma cells. (A–D) Illustration of autophagosomes and autophagolysosomes in NW5, 143B, and U2OS cells before and after BafA1 treatment. The autophagosomes were determined by electron microscopy. (E) Expression of LC3B, Beclin1, and P-ULK1 in osteosarcoma cells. The expression of LC3B, Beclin1, and P-ULK1 was determined in SaOS2, U2OS, HOS, 143B, and NW5 cells by Western blot. GAPDH served as the internal control. (F) Determination of autophagic flux in osteosarcoma cells. The expression and distribution of LC3B in NW5, 143B, U2OS, and SaOS2 cells were determined before and after BafA1 treatment. Green represents LC3B, red represents lysosomes, and blue represents DAPI. The yellow color in the merged image shows the colocalization of LC3 with lysosomes.

Fig.2 Expression of the autophagy-related genes Beclin1 and LC3B in primary tissues of osteosarcoma. (A, B) Representative illustration of Beclin1 and LC3B expression in the tumor tissue of osteosarcoma with favorable or adverse outcomes. Beclin1 and LC3B expression in osteosarcoma tumor tissues was detected by immunochemistry with antibodies against Beclin1 and LC3B. Three tumor tissues from patients with poor prognosis and three from patients with favorable prognosis are illustrated. (C, D) High levels of Beclin1 and LC3B were related to poor overall survival of osteosarcoma. (E, F) High levels of Beclin1 and LC3B were related to poor metastasis-free survival of osteosarcoma.

Fig.3 Knockdown of Beclin1 or LC3B inhibited the proliferation, invasion, and metastasis of osteosarcoma cells. (A) Validation of knockdown efficiency. (B–D) LC3B and Beclin1 knockdown inhibited the proliferation, invasion, and metastasis of 143B cells. Cell-viability (B), wound-healing (C), and Transwell (D) experiments were performed in 143 cells transfected with siRNA targeting LC3B, Beclin1, or nonspecific siRNA (N. C.). (E, F) Inhibition of autophagy by 3-MA inhibited the invasion and metastasis of 143B cells. Wound-healing (E) and Transwell (F) experiments were performed in 143 cells treated with DMSO or 3-MA.

Fig.4 Inhibition of autophagy inhibited the tumor growth and metastasis of osteosarcoma in vivo. (A, B) 3-MA inhibited the tumor growth of osteosarcoma. The tumor volumes (A) and tumor sizes (B) of 3-MA- or placebo-treated Luc-NW5 xenograft mice are shown. NW5 cells were xenografted in NOD-SCID mice via paratibial injection. The tumor-burdened mice were treated with 3-MA or placebo 20 days after xenografting.

Fig.5 Targeting LC3B- and Beclin1-sensitized osteosarcoma cells to chemotherapy. (A, B) Chemotherapy enhanced autophagy in NW5 cells. Autophagosomes and autophagolysosomes detected by electron microscopy (A) in NW5 cells treated with cisplatin and doxorubicin are shown. The statistical analysis is shown (B). (C, D) Knockdown of LC3B- and Beclin1-sensitized NW5 and 143B cells to doxorubicin chemotherapy. The NW5 (C) or 143B (D) cells transfected with N.C. siRNA or siRNA targeting LC3B or Beclin1 was treated with doxorubicin for 24 h. Cell viability was detected by CCK-8 assays. (E) Autophagy inhibition by 3-MA synergistically inhibited the cell growth of osteosarcoma cells. The IC50 of doxorubicin in DMSO- or 3-MA-treated NW cells was detected by CCK8. (F) 3-MA inhibited doxorubicin induced autophagy. The protein levels of LC3B were detected in 3-MA-, BafA1-, or doxorubicin-treated osteosarcoma cells.

Fig.6 H3K27ac signals at the regulatory regions of autophagy-related genes in metastatic and nonmetastatic osteosarcoma cells. Schematic of H3K27ac signals among the regulatory regions of Beclin1 (BECN1), MAP1LC3B (LC3B), MAP1LC3A (LC3A), and ATG5 in metastatic (LM7, MNNG, 143B, and MG63.3) and nonmetastatic (MG63, SaOS2, Hu09, and HOS) cells.

Fig.7 Inhibition of SEs inhibited autophagy and metastasis in osteosarcoma. (A) JQ-1 inhibited the expression of Beclin1 (BECN1), MAP1LC3B (LC3B), MAP1LC3A (LC3A), and ATG5 in 143B and NW5 cells. (B) JQ-1 inhibited the metastasis of 143B and NW5 cells. 143 B and NW5 cells were treated with 1 μmol/L JQ-1 for 48 h, and the expression of BECN1, MAP1LC3B, and MAP1LC3A were examined by qRT-PCR experiments. GAPDH served as internal control. Cell invasion and metastasis were examined by the Transwell assays.

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