EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma

Balinth, Seamus, Fisher, Matthew L, Hwangbo, Yon, Wu, Caizhi, Ballon, Carlos, Sun, Xueqin, Mills, Alea A (July 2022) EZH2 regulates a SETDB1/ΔNp63α axis via RUNX3 to drive a cancer stem cell phenotype in squamous cell carcinoma. Oncogene. ISSN 0950-9232

URL: https://www.ncbi.nlm.nih.gov/pubmed/35864175
DOI: 10.1038/s41388-022-02417-4


Enhancer of zeste homolog 2 (EZH2) and SET domain bifurcated 1 (SETDB1, also known as ESET) are oncogenic methyltransferases implicated in a number of human cancers. These enzymes typically function as epigenetic repressors of target genes by methylating histone H3 K27 and H3-K9 residues, respectively. Here, we show that EZH2 and SETDB1 are essential to proliferation in 3 SCC cell lines, HSC-5, FaDu, and Cal33. Additionally, we find both of these proteins highly expressed in an aggressive stem-like SCC sub-population. Depletion of either EZH2 or SETDB1 disrupts these stem-like cells and their associated phenotypes of spheroid formation, invasion, and tumor growth. We show that SETDB1 regulates this SCC stem cell phenotype through cooperation with ΔNp63α, an oncogenic isoform of the p53-related transcription factor p63. Furthermore, EZH2 is upstream of both SETDB1 and ΔNp63α, activating these targets via repression of the tumor suppressor RUNX3. We show that targeting this pathway with inhibitors of EZH2 results in activation of RUNX3 and repression of both SETDB1 and ΔNp63α, antagonizing the SCC cancer stem cell phenotype. This work highlights a novel pathway that drives an aggressive cancer stem cell phenotype and demonstrates a means of pharmacological intervention.

Item Type: Paper
CSHL Authors:
Communities: CSHL labs > Mills lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 21 July 2022
Date Deposited: 26 Jul 2022 22:42
Last Modified: 26 Jul 2022 22:42
URI: https://repository.cshl.edu/id/eprint/40689

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