Center for Cancer Biology, VIB, Leuven, Belgium.
Center for Human Genetics, KU Leuven, Herestraat 49, box 912, B-3000, Leuven, Belgium.
J Hematol Oncol. 2018 Aug 25;11(1):108. doi: 10.1186/s13045-018-0650-0.
The CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL).
Here, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex.
Our data show that knockdown of Not3, the structural components Not1/Not2, and the deadenylases twin/Pop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3.
Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.
CNOT3 蛋白是 CCR4-NOT 复合物的一个亚基，该复合物参与 mRNA 降解。我们最近在 T 细胞急性淋巴细胞白血病（T-ALL）患者中发现了 CNOT3 功能丧失突变。
在这里，我们使用不同的果蝇眼癌模型来研究 Not3（CNOT3 的同源物）和 CCR4-NOT 复合物的其他成员的潜在肿瘤抑制功能。
我们的数据表明，Not3、结构成分 Not1/Not2 和脱腺苷酶 twin/Pop2 的敲低均导致肿瘤形成增加。此外，Not3 的过表达可以减少肿瘤形成。Not3 的下调对基因表达有轻微但广泛的影响，并导致参与 DNA 复制和核糖体生物发生的基因水平升高。CycB 的上调也促成了 Not3 的肿瘤表型。在人类 T-ALL 细胞系中也得到了类似的发现，指出了 Not3 的保守功能。
总之，我们的数据确立了 Not3 和整个 CCR4-NOT 复合物作为肿瘤抑制因子的关键作用。
