EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

• DOI: 10.1038/s41467-021-27609-6
• Publication Date: 2022-01-10T11:02:59Z
• Authors: Liyuan Wang; Chan Chen; Zemin Song; Honghong Wang; Minghui Ye; Donghai Wang; Wenqian Kang; Hudan Liu; Guoliang Qing
• Keywords: Oncogene Proteins; 0301 basic medicine; N-Myc Proto-Oncogene Protein; Science; Q; Small Cell Lung Carcinoma; Article; 3. Good health; Neuroblastoma; 03 medical and health sciences; Drug Delivery Systems; Cell Line, Tumor; Humans; Enhancer of Zeste Homolog 2 Protein; Carcinoma, Small Cell

Abstract Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby promotes cancer. In current study, we show that directly interacts with both MYC family oncoproteins, and MYCN, their stabilization in a methyltransferase-independent manner. By competing against SCF FBW7 ubiquitin ligase bind counteracts FBW7-mediated MYC(N) polyubiquitination proteasomal degradation. Depletion, but not enzymatic inhibition, induces robust degradation inhibits tumor cell growth driven neuroblastoma small lung carcinoma. Here, demonstrate proteins as global oncogenic effectors pharmacologic degraders potential targeted cancer therapeutics, pointing out cancers may develop inherent resistance canonical inhibitors currently clinical development.