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

Nat Commun. 2022 Jan 10;13(1):12. doi: 10.1038/s41467-021-27609-6.


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 SCFFBW7 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carcinoma, Small Cell* / drug therapy
  • Carcinoma, Small Cell* / metabolism
  • Cell Line, Tumor
  • Drug Delivery Systems
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Humans
  • N-Myc Proto-Oncogene Protein / metabolism*
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / therapy
  • Oncogene Proteins / metabolism
  • Small Cell Lung Carcinoma / drug therapy
  • Small Cell Lung Carcinoma / metabolism


  • N-Myc Proto-Oncogene Protein
  • Oncogene Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein