» Articles » PMID: 31805991

Inhibition of the Histone Demethylase, KDM5B, Directly Induces Re-expression of Tumor Suppressor Protein HEXIM1 in Cancer Cells

Overview
Specialty Oncology
Date 2019 Dec 7
PMID 31805991
Citations 15
Authors
Affiliations
Soon will be listed here.
Abstract

Background: The tumor suppressor actions of hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) in the breast, prostate, melanomas, and AML have been reported by our group and others. Increased HEXIM1 expression caused differentiation and inhibited proliferation and metastasis of cancer cells. Historically, HEXIM1 has been experimentally induced with the hybrid polar compound HMBA, but HMBA is a poor clinical candidate due to lack of a known target, poor pharmacological properties, and unfavorable ADMETox characteristics. Thus, HEXIM1 induction is an intriguing therapeutic approach to cancer treatment, but requires better chemical tools than HMBA.

Methods: We identified and verified KDM5B as a target of HEXIM1 inducers using a chemical proteomics approach, biotin-NeutrAvidin pull-down assays, surface plasmon resonance, and molecular docking. The regulation of HEXIM1 by KDM5B and KDM5B inhibitors was assessed using chromatin immunoprecipitation assays, RT-PCR, western blotting, and depletion of KDM5B with shRNAs. The regulation of breast cancer cell phenotype by KDM5B inhibitors was assessed using western blots, differentiation assays, proliferation assays, and a mouse model of breast cancer metastasis. The relative role of HEXIM1 in the action of KDM5B inhibitors was determined by depleting HEXIM1 using shRNAs followed by western blots, differentiation assays, and proliferation assays.

Results: We have identified a highly druggable target, KDM5B, which is inhibited by small molecule inducers of HEXIM1. RNAi knockdown of KDM5B induced HEXIM1 expression, thus validating the specific negative regulation of tumor suppressor HEXIM1 by the H3K4me3/2 demethylase KDM5B. Known inhibitors of KDM5B were also able to induce HEXIM1 expression, inhibit cell proliferation, induce differentiation, potentiate sensitivity to cancer chemotherapy, and inhibit breast tumor metastasis.

Conclusion: HMBA and 4a1 induce HEXIM1 expression by inhibiting KDM5B. Upregulation of HEXIM1 expression levels plays a critical role in the inhibition of proliferation of breast cancer cells using KDM5B inhibitors. Based on the novel molecular scaffolds that we identified which more potently induced HEXIM1 expression and data in support that KDM5B is a target of these compounds, we have opened up new lead discovery and optimization directions.

Citing Articles

MAAT: a new nonparametric Bayesian framework for incorporating multiple functional annotations in transcriptome-wide association studies.

Wang H, Li X, Li T, Li Z, Sham P, Zhang Y Genome Biol. 2025; 26(1):21.

PMID: 39905509 PMC: 11796105. DOI: 10.1186/s13059-025-03485-x.


CancerHubs: a systematic data mining and elaboration approach for identifying novel cancer-related protein interaction hubs.

Ferrari I, De Grossi F, Lai G, Oliveto S, Deroma G, Biffo S Brief Bioinform. 2024; 26(1).

PMID: 39657701 PMC: 11631132. DOI: 10.1093/bib/bbae635.


KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges.

Li C, Wang W, Leung C, Yang G, Chen J Mol Cancer. 2024; 23(1):109.

PMID: 38769556 PMC: 11103982. DOI: 10.1186/s12943-024-02011-0.


Entecavir: A Review and Considerations for Its Application in Oncology.

Lourenco T, Vale N Pharmaceuticals (Basel). 2023; 16(11).

PMID: 38004468 PMC: 10675314. DOI: 10.3390/ph16111603.


HMBA ameliorates obesity by MYH9- and ACTG1-dependent regulation of hypothalamic neuropeptides.

Park S, Oh S, Kim N, Kim E EMBO Mol Med. 2023; 15(12):e18024.

PMID: 37984341 PMC: 10701615. DOI: 10.15252/emmm.202318024.


References
1.
Liu M, Casimiro M, Wang C, Shirley L, Jiao X, Katiyar S . p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A. 2009; 106(45):19035-9. PMC: 2776463. DOI: 10.1073/pnas.0910009106. View

2.
Bogen D, Wei J, Azorsa D, Ormanoglu P, Buehler E, Guha R . Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma. Oncotarget. 2015; 6(34):35247-62. PMC: 4742102. DOI: 10.18632/oncotarget.6208. View

3.
Wittmann B, Wang N, Montano M . Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors. Cancer Res. 2003; 63(16):5151-8. View

4.
Devaraj S, Fiskus W, Shah B, Qi J, Sun B, Iyer S . HEXIM1 induction is mechanistically involved in mediating anti-AML activity of BET protein bromodomain antagonist. Leukemia. 2015; 30(2):504-8. PMC: 4809433. DOI: 10.1038/leu.2015.142. View

5.
Tan J, Fogley R, Flynn R, Ablain J, Yang S, Saint-Andre V . Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma. Mol Cell. 2016; 62(1):34-46. PMC: 4836061. DOI: 10.1016/j.molcel.2016.03.013. View