Loss of SMARCB1 promotes autophagy and facilitates tumour progression in chordoma by transcriptionally activating ATG5

Abstract

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.

Loss of INI1 inhibits the expression of SIDT1 and promotes tumor progression in skull base chordoma by regulating EZH2-mediated H3K27me3

“…Investigators have also recently proposed a novel subtype of chordoma, poorly differentiated chordoma, that shows more aggressive biologic behaviors and poorer survival, and the loss of INI1 is a crucial characteristic of poorly differentiated chordoma (16,17,19). Moreover, our previous study revealed the tumor-suppressive effects of INI1 in chordoma cells, where we found that INI1 inhibited the proliferation and invasion of chordoma cells (20). However, the mechanism underlying INI1's role in chordoma has not yet been elucidated.…”

“…While earlier studies were primarily focused on the origin of INI1 loss and the identi cation of locus deletion(16, 19,38), the downstream molecular mechanism underlying INI1 action in chordoma remains almost completely unelucidated. Our previous work suggested that autophagy was involved in the function of INI1, and ATG5 was identi ed as a novel transcriptionalregulation target of INI1; rescue experiments using ATG5 siRNA further con rmed that ATG5-mediated autophagy was critical to the oncogenesis of INI1 loss (20). In this study, we examined another molecular mechanism in which INI1 regulated chordoma progression from the perspective of epigenetics.…”

“…Our previous study revealed a tumor-suppressive action of INI1 in chordoma (20), and we subsequently intended to assess whether there was a relationship between the tumor-suppressor gene INI1 and the oncogene EZH2 in chordoma cells. We analyzed the transcriptomic sequencing data of the 48 skull base chordomas and found that there was a negative correlation between the expression of INI1 and the expression of EZH2 (r = -0.5, p = 0.00035) (Figure 2A).…”

The temporal transcriptomic signature of cartilage formation

“…RNF8 promotes proliferation by upregulating c-Myc expression via the Wnt/β-catenin pathway, one of the fundamental signaling cascades in development and homeostasis (51). SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 ( SMARCB1 ) is a tumor suppressor which regulates ATG5, an essential autophagy-related gene that plays a vital role in autophagosome formation (52). During preadipocyte proliferation and differentiation, FoxO6 directly targets and induces expression of cyclin G2 ( CCNG2 ) (53).…”

“…While some of the TFs picked up in this study that are known interacting partners of FOS, is a tumor suppressor which regulates ATG5, an essential autophagy-related gene that plays a vital role in autophagosome formation (52). During preadipocyte proliferation and differentiation, FoxO6 directly targets and induces expression of cyclin G2 (CCNG2) (53).…”