Small-molecule induction of phospho-eIF4E sumoylation and degradation via targeting its phosphorylated serine 209 residue

Zhang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2019

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.

Section: Discussionsupporting

confidence: 52%

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

Zhang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2019

“…As far as we known, HHT has multiple drug targets. Ying Gu et al reported that p-eIF4E was a drug target of HHT [4]. Instead, we found myosin-9 was one of the critical targets in AML cell lines.…”

Section: Introductioncontrasting

confidence: 65%

Prognostic impact of MYH9 expression on patients with acute myeloid leukemia

Wang

Zhu

et al. 2016

Oncotarget

MYH9 expression has previously been demonstrated as an independent predictor of clinical outcome in solid tumors. However, the prognostic relevance of MYH9 expression in acute myeloid leukemia is still unclear. Here, we found high MYH9 expressers were seen more frequently in females and more frequently in M4 morphology. We also found high MYH9 expressers had lower percentage of bone marrow blasts. In addition, overexpression of MYH9 was associated with an inferior overall survival. Notably, distinct microRNA signatures were seen in high MYH9 expressers. These results were also validated in an independent cohort of AML patients using the published data. In conclusion, gene of MYH9 expression might serve as a reliable predictor for overall survival in AML patients.

“…Five best druggable sites of the FEN1 protein were predicted using our in-house developed Druggable Site Prediction (DSP) algorithm (Gu et al, 2015) (Fig. 3b).…”

Section: Resultsmentioning

confidence: 99%

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

et al. 2016

Self Cite

DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.