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 EZH2 promotes cancer. In the current study, we show that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCF ubiquitin ligase to bind MYC and MYCN, EZH2 counteracts FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induces robust MYC(N) degradation and inhibits tumor cell growth in MYC(N) driven neuroblastoma and small cell lung carcinoma. Here, we demonstrate the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
Transcription factors collaborate with epigenetic regulatory factors to orchestrate cardiac differentiation for heart development, but the underlying mechanism is not fully understood. Here, we report that GATA-6 induces cardiac differentiation but peroxisome proliferator-activated receptor α (PPARα) reverses GATA-6-induced cardiac differentiation, possibly because GATA-6/PPARα recruits the polycomb protein complex containing EZH2/Ring1b/BMI1 to the promoter of the cardiac-specific α-myosin heavy chain (α-MHC) gene and suppresses α-MHC expression, which ultimately inhibits cardiac differentiation. Furthermore, Ring1b ubiquitylates PPARα and GATA-6.
Division of Cancer Biology, CSIR-Central Drug Research Institute (CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India. Electronic address:
Cancer cells experience multiple reversible changes during their metastatic spread. Epigenetic reprogramming, being reversible, has emerged as a critical driver of cancer metastasis. Epigenetic modulator Enhancer of Zeste homolog 2 (EZH2) is an important candidate for such reprogramming events.
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Urology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Cisplatin (CDDP) resistance has been established to significantly impact Bladder Cancer (BCa) therapy. On the other hand, the crucial regulatory involvement of SIRT7 and EZH2 in bladder cancer development is well known. Herein, the collaborative regulatory roles and underlying mechanisms of SIRT7 and EZH2 in CDDP resistance in bladder cancer were explored.
Objective: Liquid-liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and to confirm their effects on tumor progression.
Methods: Based on public transcriptomic data, this study screened LLPS- and immune-related genes for MM-derived plasma cells.
Background: The "loss of control" over drug consumption, present in opioid use disorder (OUD) and known as escalation of intake, is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, may impact the trajectory of fentanyl intake over time. Moreover, it is unclear if distinct escalation phenotypes may be driven by genetic markers predictive of OUD susceptibility.
