Department of Biological Sciences, Inha University, Incheon 22212, Korea.
Mol Cells. 2019 Jan 31;42(1):17-27. doi: 10.14348/molcells.2018.0329. Epub 2019 Jan 2.
Ubiquitin-specific protease 44 (USP44) has been implicated in tumor progression and metastasis across various tumors. However, the function of USP44 in prostate cancers and regulatory mechanism of histone-modifying enzymes by USP44 in tumors is not well-understood. Here, we found that enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 methyltransferase, is regulated by USP44. We showed that EZH2 is a novel target of USP44 and that the protein stability of EZH2 is upregulated by USP44-mediated deubiquitination. In USP44 knockdown prostate cancer cells, the EZH2 protein level and its gene silencing activity were decreased. Furthermore, USP44 knockdown inhibited the tumorigenic characteristics and cancer stem cell-like behaviors of prostate cancer cells. Inhibition of tumorigenesis caused by USP44 knockdown was recovered by ectopic introduction of EZH2. Additionally, USP44 regulates the protein stability of oncogenic EZH2 mutants. Taken together, our results suggest that USP44 promotes the tumorigenesis of prostate cancer cells partly by stabilizing EZH2 and that USP44 is a viable therapeutic target for treating EZH2-dependent cancers.
泛素特异性蛋白酶 44（USP44）已被牵连到各种肿瘤的肿瘤进展和转移中。然而，USP44 在前列腺癌中的功能以及 USP44 对肿瘤中组蛋白修饰酶的调控机制尚不清楚。在这里，我们发现增强子结合蛋白 2（EZH2），一种组蛋白 H3 赖氨酸 27 甲基转移酶，受 USP44 调节。我们表明 EZH2 是 USP44 的一个新靶标，USP44 通过去泛素化来上调 EZH2 的蛋白稳定性。在 USP44 敲低的前列腺癌细胞中，EZH2 蛋白水平及其基因沉默活性降低。此外，USP44 敲低抑制了前列腺癌细胞的致瘤特征和癌症干细胞样行为。通过异位引入 EZH2，恢复了 USP44 敲低引起的肿瘤发生抑制。此外，USP44 调节致癌 EZH2 突变体的蛋白稳定性。总之，我们的研究结果表明，USP44 通过稳定 EZH2 促进前列腺癌细胞的肿瘤发生，并且 USP44 是治疗依赖 EZH2 的癌症的可行治疗靶点。
