EZH2-mediated development of therapeutic resistance in cancer.

Eswar Shankar, Sanjay Gupta, Parminder Kaur

Journal: Cancer letters 2024;586():216706

PMID: 38331087

Full Text on Elsevier Science View on PubMed

Abstract

Enhancer of zeste homolog 2 (EZH2) regulates gene expression and plays a definite role in cell proliferation, apoptosis, and senescence. Overexpression of EZH2 has been found in various human malignancies, including prostate, breast, and ovarian cancers, and is associated with increased metastasis and poor prognosis. EZH2 catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) as a canonical role in a PRC2-dependent manner. This mechanism silences various tumor suppressor genes through EZH2-mediated histone lysine methyltransferase activity. As a non-canonical role, EZH2 partners with other signaling molecules to undergo post-translational modification to orchestrate its function as a co-activator playing a critical role in cancer progression. Dysregulation of EZH2 has also been associated with therapeutic resistance in cancer cells. Given the role of EZH2 in promoting carcinogenesis and therapy resistance, both canonical and non-canonical EZH2 inhibitors have been used to combat multiple cancer types. Moreover, combining EZH2 inhibitors with other therapeutic modalities have shown to enhance the therapeutic efficacy and overcome potential resistance mechanisms in these cancerous cells. Therefore, targeting EZH2 through canonical and non-canonical modes appears to be a promising therapeutic strategy to enhance efficacy and overcome resistance in multiple cancers.

Address: Department of Urology, Case Western Reserve University, Cleveland, OH, 44016, USA; The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44016, USA. Electronic address: [email protected].; Department of Urology, Case Western Reserve University, Cleveland, OH, 44016, USA; Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. Electronic address: [email protected].; Department of Urology, Case Western Reserve University, Cleveland, OH, 44016, USA; The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44016, USA; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44016, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, 44016, USA; Department of Nutrition, Case Western Reserve University, Cleveland, OH, 44016, USA; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA. Electronic address: [email protected].

DOI: 10.1016/j.canlet.2024.216706

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MeSH Terms: Male, Female, Humans, Enhancer of Zeste Homolog 2 Protein, Drug Resistance, Neoplasm, Histones, Ovarian Neoplasms, Histone-Lysine N-Methyltransferase, Cell Line, Tumor