State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China.
Department of Colorectal Surgery State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat-sen University Cancer Center Guangzhou Guangdong 510060 P. R. China.
Adv Sci (Weinh). 2021 Mar 15;8(10):2004344. doi: 10.1002/advs.202004344. eCollection 2021 May.
Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including , , , and . DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.
结直肠癌是全球最常见的癌症之一，常伴有肿瘤细胞的失控增殖。使用全基因组 RNAi 策略筛选出的假尿嘧啶核苷合酶 1（DKC1）是一种先前未被识别的关键调节因子，可促进结直肠癌细胞增殖。DKC1 的强制表达，而不是其催化失活突变体 D125A，可加速体外和体内细胞生长。DKC1 敲低或其抑制剂吡唑呋喃酮可减弱细胞增殖。蛋白质组学、RNA 免疫沉淀（RIP）-seq 和 RNA 降解分析表明，DKC1 结合并稳定几种核糖体蛋白（RPs）的 mRNA，包括 、 、 和 。DKC1 耗竭可显著加速这些 RPs 的 mRNA 降解，这介导了 DKC1 的致癌功能。有趣的是，这些由 DKC1 调节的 RPs 还与 HRAS 相互作用并抑制 RAS/RAF/MEK/ERK 通路。吡唑呋喃酮和 trametinib 联合可协同抑制体外和体内结直肠癌细胞生长。此外，与相邻正常组织相比，结直肠癌组织中 DKC1 的表达明显上调。DKC1 表达较高的结直肠癌患者的总生存期和无进展生存期结果始终较差。综上所述，这些数据表明 DKC1 是结直肠癌的必需基因和候选治疗靶点。
