LINC00922 decoys SIRT3 to facilitate the metastasis of colorectal cancer through up-regulation the H3K27 crotonylation of ETS1 promoter

Abstract

Background Lysine crotonylation (Kcr) is up-regulation in colorectal cancer (CRC) tissues, while its specific contribution remains uncertain. This study aimed to elucidate the role and mechanism of crotonylation on Lys27 of histone H3 (H3K27cr) in facilitating CRC metastasis. Methods Immunohistochemistry was employed to investigate the correlation between H3K27cr and CRC metastasis. Both in vitro and in vivo assays employing loss function or gain function approaches were conducted to elucidate the role of LINC00922 in promoting CRC metastasis. ScRNA-seq analysis and immunoprecipitation analyses were employed to explore the underlying mechanism by which LINC00922 facilitates CRC metastasis through H3K27cr. Results Clinically, H3K27cr was upregulated in metastatic CRC tissues and positively correlated with advanced clinical stages. Functionally, knockdown of LINC00922 inhibited migration of CRC cells both in vitro and in vivo. Furthermore, the supplementation of NaCr restored the migration and invasion levels of LINC00922 stable knockdown cells by restoring the H3K27cr level. Mechanistically, LINC00922 promoted invasion and migration through H3K27cr mediated cell adhesion molecules (CAMs) in epithelial cells. Notably, LINC00922 interacted with the protein sirtuin 3 (SIRT3) and obstructed its binding to the promoter region of ETS1, leading to an elevation in the level of H3K27cr in this promoter region and the subsequent activation of ETS1 transcription. Conclusions Our findings uncovered a novel regulatory function of H3K27cr, regulated by LINC00922, in facilitating CRC metastasis. This discovery contributed to a deeper comprehension of the involvement of histone crotonylation in the metastatic process of CRC.

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

“…Given the results on SIRT3 modulation and taking into account the debatable role played by this sirtuin in CRC carcinogenesis [ 37 , 42 , 46 – 48 ], the effects of SIRT3 silencing (siSIRT3) during iSGLT2 treatment were explored (Fig. 6 and Fig.…”

Mitochondrial fusion–fission dynamics and its involvement in colorectal cancer

“…However, excessive fission is believed to have a negative impact on the viability of CRC cells. SIRT3 and SIRT1 are deacetylases located in mitochondria that promote CRC proliferation and metastasis [ 59 , 60 ]. SIRT3 regulates CRC stress response by modulating mitochondrial fission, and SIRT3 deficiency triggers lethal mitochondrial fission through the inhibition of the Akt/PTEN pathway [ 61 ].…”