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

Our plain-English summary of SMG6 regulates DNA damage and cell survival in Hippo pathway kinase LATS2-inactivated malignant mesothelioma, by K. Suzuki, M. Tange, R. Yamagishi, et al (Cell Death Discovery, 2022).

The study

• Authors: K. Suzuki, M. Tange, R. Yamagishi, H. Hanada, S. Mukai, T. Sato, T. Tanaka, T. Akashi, K. Kadomatsu, T. Maeda, T. Miida, I. Takeuchi, H. Murakami, Y. Sekido, Y. Murakami-Tonami
• Journal: Cell Death Discovery
• Published: 2022;8(1):446
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

© 2022. The Author(s).

In plain English

This was a laboratory study of mesothelioma cell biology, not a study of people exposed to asbestos. The authors knocked down or knocked out the Hippo pathway kinases LATS1 and LATS2 in immortalized human mesothelial cells (HOMC-D4, MeT-5A), and also studied the mesothelioma lines Y-MESO-12 and Y-MESO-27 (the latter expressing neither LATS1 nor LATS2) and, separately, the NF2-mutant lines NCI-H2052 and NCI-H2373. LATS1 and LATS2 knockout cells both resisted cisplatin, LATS2 knockout cells more so; LATS2 knockout cells were only slightly more resistant to hydrogen peroxide than controls. Knockdown of SMG6 reduced the viability of LATS2-inactive cells (synthetic lethality), increased gamma-H2AX foci and apoptosis, and required nuclear YAP1/TAZ activity but not the nonsense-mediated mRNA decay pathway. Knockdown or inhibition of TERT also reduced the viability of LATS2-inactive cells, and the authors reported that this depended on TERT's RNA-dependent DNA polymerase activity. In mice given Y-MESO-27 cells in the thoracic cavity, BIBR1532 (2 mg/kg, twice weekly, n = 5 per group) significantly reduced tumour mass after day 17. The authors proposed SMG6 and TERT as candidate molecular targets for LATS2-inactivated cancers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experimental study using human cell lines (gene knockdown/knockout, drug treatment) with an in vivo mouse tumour model
• Who was studied: Human immortalized mesothelial cell lines (MeT-5A, HOMC-D4) and malignant mesothelioma cell lines (Y-MESO-12, Y-MESO-27, NCI-H2052, NCI-H2373), plus six-week-old female NOD/Shi-scid IL-2Rgamma-null (NOG) mice
• Exposure: Genetic inactivation of LATS1 and/or LATS2, knockdown of SMG6, TERT and other NMD factors, overexpression of mutant SMG6, YAP S127A, TAZ S89A and hTERT variants, and treatment with cisplatin, hydrogen peroxide and TERT inhibitors (BIBR1532, trichostatin, doxorubicin, TMPyP4, suramin, VX-222)
• Main results:
  • In MeT-5A cells, both LATS1 and LATS2 knockout cells showed cisplatin resistance, with LATS2 knockout cells more resistant than LATS1 knockout cells
  • With hydrogen peroxide, LATS1 knockout cells behaved like controls and LATS2 knockout cells were only slightly more resistant
  • SMG6 knockdown reduced viability of LATS2-inactive cells, including the LATS1/2-negative mesothelioma line Y-MESO-27
  • In LATS2 knockout cells, SMG6 knockdown increased DNA damage foci and apoptosis, with only modest effects in LATS1 knockout cells
  • Knockdown of NMD factors other than SMG6 did not reduce viability of LATS2-inactive cells
  • TERT knockdown reduced viability of the LATS2-inactive Y-MESO-27 cells, while Y-MESO-12 cells expressing LATS2 were similar to controls
  • TERT inhibitors with RdDP-inhibitory function reduced viability only of LATS2 knockout cells; the RdRP-specific inhibitors TMPyP4 and VX 222 did not reduce viability of any cell at the doses tested
  • In mice implanted with LATS2-mutated Y-MESO-27 cells, BIBR1532 (2 mg/kg, n = 5, versus HPMC n = 5) significantly reduced tumour mass after day 17
  • SMG6 knockdown also reduced viability in the NF2-mutant cell lines H2052 and H2373
• The authors' conclusion: The authors concluded that the findings suggest an interaction between the Hippo and TERT signalling pathways and proposed SMG6 and TERT as candidate molecular targets for LATS2-inactivated cancers such as malignant mesothelioma
• Limitations the authors state:
  • The authors stated that the mechanism by which inhibiting TERT RdDP activity causes nuclear DNA damage in LATS2 knockout cells, and the role of SMG6 nuclease activity in it, remain unknown
  • The authors stated that SMG6's involvement in DNA repair has not been directly demonstrated
  • The authors stated that the relationship between NF2 mutations and SMG6/TERT expression needs further investigation
  • The authors stated that further mechanistic work and more detailed in vivo studies are needed

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Tumor Suppressor Gene, Translocation.

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