Open AccessLoss of SMARCB1 promotes autophagy and facilitates tumour progression in chordoma by transcriptionally activating ATG5
Author(s) -
Li Mingxuan,
Shen Yutao,
Xiong Yujia,
Wang Shuai,
Li Chuzhong,
Bai Jiwei,
Zhang Yazhuo
Publication year - 2021
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.13136
Subject(s) - smarcb1 , atg5 , chordoma , autophagy , biology , cancer research , transcription factor , chromatin remodeling , pathology , medicine , genetics , apoptosis , gene
Objectives SWI/SNF‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 (SMARCB1) loss is associated with a poor prognosis in chordoma, while the mechanism remains largely unclear. Here, we aim to explore the function and regulatory mechanisms of SMARCB1 in chordoma. Materials and Methods The effect of SMARCB1 on chordoma cells was investigated in vitro and in vivo. Chromatin immunoprecipitation (ChIP) sequencing was used to investigate the mechanisms of SMARCB1 in chordoma. The association between SMARCB1 and autophagy was validated by Western blot, immunofluorescence and transmission electron microscopy. In addition, the ATG5 expression in chordoma tissue was assessed using immunohistochemistry and correlated with patient survival. Results SMARCB1 inhibited the malignant phenotype of chordoma cells in vitro and in vivo, supporting a tumour suppressor role of SMARCB1 in chordoma. ATG5‐mediated autophagy was identified as a potential downstream pathway of SMARCB1. Mechanistically, SMARCB1 bound directly to the ATG5 promoter and epigenetically inhibited its transcription, which decreased ATG5 expression and impaired autophagy. Additionally, autophagy inhibitor chloroquine had a potential anti‐cancer effect on chordoma cells in vitro. Moreover, high ATG5 expression was observed in recurrent chordoma patients, which independently correlated with adverse outcomes. Conclusions Taken together, our results revealed that the SMARCB1/ATG5 axis is a promising therapeutic target for chordoma and autophagy inhibitors may be effective agents for chordoma treatment.