HMGB1 ubiquitination inhibition and extracellular secretion, mediated by m6A modified-exosomal lncRNA MALAT1, creates a communication between NK92-MI cells and tumor cells to aggravate acute lymphoblastic leukemia.
TL;DR
All cells-derived exosomal MALAT1 was up-regulated by METTL14-mediated m6A modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells.
Abstract
Background
MALAT1 has been validated to favor the progression of acute lymphoblastic leukemia (ALL), but its detailed mechanism remains obscure. This study explored the functional roles of ALL cells-derived exosomal MALAT1 in chemoresistance and malignant growth of ALL cells, as well as its underlying mechanisms.
Methods
The expression of target molecules was evaluated by qRT-PCR, Western blotting, immunofluorescence, and immunohistochemical staining. CCK-8, EdU staining and flow cytometry were conducted to determine cell proliferation and apoptosis. RIP, RNA-pull down, Co-IP, and MeRIP were used to investigate molecular mechanisms. ALL cells were injected into nude mice to evaluate in vivo tumor formation.
Results
MALAT1 and methyltransferase-like 14 (METTL14) were up-regulated in ALL, which exhibited a positive correlation. METTL14-mediated m6A modification raised MALAT1 stability and expression, and consequently facilitated ALL cell growth and apoptosis inhibition. Furthermore, MALAT1 was packaged into ALL cells-derived exosomes by hnRNPA2B1, and then transferred to NK92-MI cells. Exosomal MALAT1 suppressed tripartite motif-containing 27 (TRIM27)-mediated ubiquitination of High-mobility group box 1 (HMGB1) in NK92-MI cells, thereby leading to adriamycin resistance and malignant development of ALL cells.
Conclusion
ALL cells-derived exosomal MALAT1 was up-regulated by METTL14-mediated m6A modification, and subsequently restrained HMGB1 ubiquitination and degradation in NK92-MI cells, which resulted in adriamycin resistance and malignant growth of ALL cells. Therefore, inhibition of METTL14/MALAT1/HMGB1 axis might be a therapeutic strategy for ALL patients. HIGHLIGHTS (1)METTL14 and MALAT1 were positively correlated in ALL samples.(2)METTL14 increased MALAT1 stability and expression in an IGF2BP1-mediated m6A manner.(3)ALL cells transferring exosomal MALAT1 suppressed TRIM27-mediated HMGB1 ubiquitination in NK92-MI cells.(4)HMGB1 silencing in NK92-MI cells enhanced adriamycin sensitivity of ALL cells.(5)MALAT1/HMGB1 axis inhibition delayed in vivo ALL growth via NK cell activation.