Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, NY, USA.
Oncogene. 2022 Aug;41(35):4130-4144. doi: 10.1038/s41388-022-02417-4. Epub 2022 Jul 21.
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.
增强子结合锌指蛋白 2（EZH2）和 SET 域分裂蛋白 1（SETDB1，也称为 ESET）是参与多种人类癌症的致癌甲基转移酶。这些酶通常通过分别甲基化组蛋白 H3 K27 和 H3-K9 残基来作为靶基因的表观遗传抑制剂发挥作用。在这里，我们表明 EZH2 和 SETDB1 对于 SCC 细胞系 HSC-5、FaDu 和 Cal33 的增殖是必需的。此外，我们发现这两种蛋白质在侵袭性干细胞样 SCC 亚群中高度表达。EZH2 或 SETDB1 的缺失会破坏这些干细胞样细胞及其相关的球体形成、侵袭和肿瘤生长表型。我们表明，SETDB1 通过与 ΔNp63α 合作来调节这种 SCC 干细胞表型，ΔNp63α 是 p53 相关转录因子 p63 的致癌同工型。此外，EZH2 是 SETDB1 和 ΔNp63α 的上游，通过抑制肿瘤抑制因子 RUNX3 来激活这些靶标。我们表明，用 EZH2 的抑制剂靶向该途径会导致 RUNX3 的激活以及 SETDB1 和 ΔNp63α 的抑制，从而拮抗 SCC 癌症干细胞表型。这项工作强调了一个新的途径，该途径驱动侵袭性癌症干细胞表型，并展示了一种药理学干预的方法。
