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?Np63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.

ABSTRACT: ?Np63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ?Np63 protein stability through the E3 ubiquitin ligase, Fbw7. ?Np63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas, and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.

SUBMITTER: Napoli M

PROVIDER: S-EPMC4908836 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.

Napoli Marco M Venkatanarayan Avinashnarayan A Raulji Payal P Meyers Brooke A BA Norton William W Mangala Lingegowda S LS Sood Anil K AK Rodriguez-Aguayo Cristian C Lopez-Berestein Gabriel G Vin Harina H Duvic Madeleine M Tetzlaff Michael B MB Curry Jonathan L JL Rook Alain H AH Abbas Hussein A HA Coarfa Cristian C Gunaratne Preethi H PH Tsai Kenneth Y KY Flores Elsa R ER

Cancer cell 20160601 6

ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identif ...[more]

PMID: 27300436

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Project description:Purpose: Non-Small-Cell Lung Cancer (NSCLC) has gained resistance to common chemo- and radiotherapy due to the oncogenic K-RAS mutations. In this work, lactonic sophorolipids (LSL), a constituent of natural sophorolipids known to inhibit histone deacetylase (HDAC) activity, is used to evaluate its potential anticancer property for the treatment of NSCLC. In addition, ganetespib (GT), a Hsp90 inhibitor, is used for its known antitumor activity in several K-RAS mutant NSCLC cells. We propose, a functional anti-oxidant nanomedicine composed of nanoceria (NC) encapsulated with two-drug cocktail LSL and GT for the assessment of therapeutic efficacy of LSL and targeted combination therapy of NSCLC. NC is an excellent redox platform specifically used to supplement the therapeutic potency of these drugs to target both HDAC inhibition and Hsp90 signaling pathways in NSCLC. Methods: Polyacrylic acid-coated nanoceria (PNC) was formulated and folic acid was conjugated on the surface of PNC using "click" chemistry to target NSCLC and to minimize adverse side effects. Solvent diffusion method was used for the encapsulation of individual drugs and co-encapsulation of drug-cocktail along with an optical dye DiI for diagnosis. We hypothesized that the therapeutic efficacy of LSL will be synergistically accelerated by the inhibition of Hsp90 mechanism of GT and redox activity of NC. Results: For the targeted therapy of NSCLC, A549 cells were used and Chinese hamster ovary (CHO) cells were used as healthy control cells. Results showed more than 40% cells were dead within 24 h when treated with LSL nanodrug. When combined with GT, enhanced ROS signals were detected and more than 80% reduction in cell viability was recorded within 24 h of incubation. Treatments with NC without any drug showed minimal toxicity. Migration assays indicate that the highly metastatic nature of NSCLC is successfully restricted by this combination approach. To validate the effectiveness of this combination therapy various cell-based assays including detection of apoptosis, necrosis and HDAC inhibition of LSL were performed. Conclusion: Functional nanoceria with drug-cocktail LSL and GT is successfully developed for the targeted treatment of undruggable NSCLC. The fluorescence modality helps monitoring the drugs delivery. Results demonstrate the potential therapeutic efficacy of LSL, which is synergistically accelerated by the Hsp90 inhibition mechanism of GT and redox activity of NC.

Dataset Information

?Np63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.

Publications

ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.

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