Evron Tamar, Caspi Michal, Kazelnik Michal, Shor-Nareznoy Yarden, Armoza-Eilat Shir, Kariv Revital, Manber Zohar, Elkon Ran, Sklan Ella H, Rosin-Arbesfeld Rina
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Oncogenesis. 2021 Sep 22;10(9):63. doi: 10.1038/s41389-021-00354-7.
The Wnt signaling pathways play fundamental roles during both development and adult homeostasis. Aberrant activation of the canonical Wnt signal transduction pathway is involved in many diseases including cancer, and is especially implicated in the development and progression of colorectal cancer. Although extensively studied, new genes, mechanisms and regulatory modulators involved in Wnt signaling activation or silencing are still being discovered. Here we applied a genome-scale CRISPR-Cas9 knockout (KO) screen based on Wnt signaling induced cell survival to reveal new inhibitors of the oncogenic, canonical Wnt pathway. We have identified several potential Wnt signaling inhibitors and have characterized the effects of the initiation factor DExH-box protein 29 (DHX29) on the Wnt cascade. We show that KO of DHX29 activates the Wnt pathway leading to upregulation of the Wnt target gene cyclin-D1, while overexpression of DHX29 inhibits the pathway. Together, our data indicate that DHX29 may function as a new canonical Wnt signaling tumor suppressor and demonstrates that this screening approach can be used as a strategy for rapid identification of novel Wnt signaling modulators.
Wnt信号通路在发育和成人稳态过程中均发挥着重要作用。经典Wnt信号转导通路的异常激活与包括癌症在内的多种疾病相关，尤其与结直肠癌的发生和发展有关。尽管已进行了广泛研究，但仍不断有参与Wnt信号激活或沉默的新基因、机制和调节因子被发现。在此，我们基于Wnt信号诱导的细胞存活进行了全基因组规模的CRISPR-Cas9基因敲除（KO）筛选，以揭示致癌性经典Wnt通路的新抑制剂。我们鉴定出了几种潜在的Wnt信号抑制剂，并对起始因子解旋酶DExH盒蛋白29（DHX29）对Wnt级联反应的影响进行了表征。我们发现敲除DHX29可激活Wnt通路，导致Wnt靶基因细胞周期蛋白D1上调，而DHX29过表达则抑制该通路。总之，我们的数据表明DHX29可能作为一种新的经典Wnt信号肿瘤抑制因子发挥作用，并证明这种筛选方法可作为快速鉴定新型Wnt信号调节因子的策略。
