Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor

Abstract

Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin−/Sca-1−/c-kit+; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65–NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on theMYCgene. Moreover, HHT significantly decreases the expression ofKIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.

Homoharringtonine Inhibits Allergic Inflammations by Regulating NF-κB-miR-183-5p-BTG1 Axis

“…HHT binds to NF-κB repressing factor ( Chen et al., 2019 ). AD activates NF-κB signaling in Nc/Nga mouse model ( Sung and Kim, 2018 ).…”

“…HHT binds to NF-κB repressing factor (NKRF) ( Chen et al., 2019 ). Second double-strand RNA-binding motif (DSRM2) domain of NKRF is necessary for binding of HHT to NKRF ( Chen et al., 2019 ).…”

“…HHT binds to NF-κB repressing factor (NKRF) ( Chen et al., 2019 ). Second double-strand RNA-binding motif (DSRM2) domain of NKRF is necessary for binding of HHT to NKRF ( Chen et al., 2019 ). HHT shifts NKRF from the nucleus to the cytoplasm, strengthens the p65-NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the MYC gene ( Chen et al., 2019 ).…”

“…Apoptotic effect of HHT is dependent on myosin-9 ( Zhang et al., 2016 ). HHT decreases the expression of KIT , a frequently mutated and/or highly expressed gene in t (8; 21) Acute Myeloid Leukemia (AML), by decreasing the expression of c-myc ( Chen et al., 2019 ).…”

Complementary and Alternative Treatments for Cancer Prevention and Cure (Part 1)

“…Mcl-1 through glycogen synthase kinase-3β (GSK3β) [217]. Deregulates MYC transcriptional expression by directly binding NF-κB repressing factor and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens [218]. disruption [223,224].…”