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

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.

Chromatin Accessibility Landscape of Human Triple-negative Breast Cancer Cell Lines Reveals Variation by Patient Donor Ancestry

“…Specifically in promoters, we identified 491 genes that were differentially accessible in EA and 1,001 that were differentially accessible in AA, with an increased access to them for TFs. Within promoter regions, the top DEGs upregulated in EA was MAGI1 , a junctional scaffold protein that acts as a tumor suppressor in the context breast cancer through inhibition of the p38 stress pathway ( 52 ), and SMG6 , which has been implicated in DNA repair and telomere maintenance ( 53 ). The top DEGs upregulated in AA was endoplasmic reticulum-associated protein ZDHHC1 , implicated in innate immune response and a positive regulator of the STING pathway ( 54 ), and ADAP1 , which has been shown to promote cancer progression by inducing cell migration and invasion ( 55 ).…”

The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma

“…BAP1 alteration has been most commonly found in patients with immune-activated MPMs and has been strongly associated with a favorable outcome for these patients, indicating subtype-specific prognostic value [50]. LATS2 mutation or inactivation is a positive regulator of mesothelioma proliferation via constitutively activating YAP and Hippo signaling pathways [51]. Considering the differentiation of M2-like TAMs and the importance of specific targeted therapy, we explored specific gene signatures for the M1 and the M2 subpopulations.…”