Suzuki Koya, Tange Masaki, Yamagishi Ryota, Hanada Hiroyuki, Mukai Satomi, Sato Tatsuhiro, Tanaka Takeshi, Akashi Tomohiro, Kadomatsu Kenji, Maeda Tohru, Miida Takashi, Takeuchi Ichiro, Murakami Hiroshi, Sekido Yoshitaka, Murakami-Tonami Yuko
Department of Clinical Laboratory of Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Cell Death Discov. 2022 Nov 5;8(1):446. doi: 10.1038/s41420-022-01232-w.
Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes and it is difficult to target these genes directly at a molecular level. We searched for the gene which showed synthetic lethal phenotype with LATS2, one of the MM causative genes and one of the kinases in the Hippo pathway. Here we showed that knockdown of SMG6 results in synthetic lethality in LATS2-inactivated cells. We found that this synthetic lethality required the nuclear translocation of YAP1 and TAZ. Both are downstream factors of the Hippo pathway. We also demonstrated that this synthetic lethality did not require SMG6 in nonsense-mediated mRNA decay (NMD) but in regulating telomerase reverse transcriptase (TERT) activity. In addition, the RNA-dependent DNA polymerase (RdDP) activity of TERT was required for this synthetic lethal phenotype. We confirmed the inhibitory effects of LATS2 and SMG6 on cell proliferation in vivo. The result suggests an interaction between the Hippo and TERT signaling pathways. We also propose that SMG6 and TERT are novel molecular target candidates for LATS2-inactivated cancers such as MM.
许多与恶性间皮瘤（MM）相关的基因已被鉴定为肿瘤抑制基因，在分子水平上直接靶向这些基因具有一定难度。我们寻找了与MM致病基因之一、Hippo信号通路中的激酶之一LATS2呈现合成致死表型的基因。在此我们表明，敲低SMG6会导致LATS2失活细胞出现合成致死现象。我们发现这种合成致死需要YAP1和TAZ的核转位，二者均为Hippo信号通路的下游因子。我们还证明，这种合成致死在无义介导的mRNA降解（NMD）过程中不需要SMG6，但在调节端粒酶逆转录酶（TERT）活性方面需要SMG6。此外，这种合成致死表型需要TERT的RNA依赖性DNA聚合酶（RdDP）活性。我们在体内证实了LATS2和SMG6对细胞增殖的抑制作用。该结果提示Hippo信号通路与TERT信号通路之间存在相互作用。我们还提出，对于LATS2失活的癌症如MM，SMG6和TERT是新的分子靶点候选物。
