SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16809
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: Suzuki Koya 順天堂大学, 大学院医学研究科, 博士研究員 (40788551)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 悪性中皮腫 / 合成致死 / LATS2 / SMG6 / TERT / Hippo経路

Outline of Final Research Achievements

Many genes responsible for Malignant mesothelioma (MM) have been identified as tumor suppressor genes including in the LATS2, which is one of the kinases in the Hippo pathway, and it is difficult to target these genes directly at a molecular level. 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 with SMG6 interaction. 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.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

LATS2は、悪性中皮腫だけでなく前立腺がん、腎細胞がん、胆管がんをはじめ複数種のがんにおいて不活性変異が報告されている。本研究では、LATS2変異悪性中皮腫に対する合成致死標的としてSMG6/TERTの阻害によって細胞死の誘導を明らかにした。さらにLATS2変異を有する他臓器のがんに対してSMG6、TERTの阻害によってがん細胞を死滅させることが期待される。