Here, we unraveled a novel mode of action of the LSD1 inhibitors MC2580 and DDP-38003, showing that they can induce differentiation of AML cells through the downregulation of the chromatin protein GSE1...Moreover, we show that LSD1 inhibitors lead to the reduced binding of GSE1 to these promoters, activating transcriptional programs that trigger myeloid differentiation. Our study offers new insights into GSE1 as a novel therapeutic target for AML.
Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.
Moreover, the alterations caused by OTUB2 overexpression were partly inversed by KDM1A knockdown and in turn KDM1A overexpression reversed the changes induced by OTUB2 shRNA. Taken together, we demonstrate that OTUB2 may serve as a vital driver in GC tumorigenesis by enhancing KDM1A-mediated stem cell-like properties.
In vivo xenograft experiments confirmed that intraperitoneal administration of ZY0511 significantly suppressed SU-DHL-6 xenograft tumor growth in vivo. In conclusion, our findings identify that ZY0511 inhibits DLBCL growth both in vitro and in vivo via the induction of apoptosis and autophagy, and LSD1 inhibitor might be a promising strategy for treating DLBCL.
Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
Cotransfection of KDM1A and DACT1 overexpression could reverse the increased cell proliferation and migration ability induced by KDM1A overexpression. KDM1A can downregulate DACT1 expression through histone deacetylation and therefore suppress the proliferation and migration of cervical cancer cells.