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Loss of LATS1 and LATS2 promotes ovarian tumor formation by enhancing AKT activity and PD-L1 expression

ABSTRACT: High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and ultimately resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion and stemness and epithelial–mesenchymal transition (EMT) characteristics. Knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE291871 | GEO | 2025/03/18

REPOSITORIES: GEO

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Project description:Background: Post-transcriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. Modifications to m6A are dynamic and reversible in cancer cells and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of m6A methylation in the Hippo pathway, a key pathway involved in cell proliferation and metabolism. Methods: First, a combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal the map of m6A modifications in breast cancer tissues and cells. Secondly, we identified the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells by performing RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis. The expression and biological functions of METTL3 and YTHDF2 were confirmed in breast cancer cell lines in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway could be affected by m6A regulation of LATS1 in breast cancer cells. Results: We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. Conclusions: In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

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Loss of LATS1 and LATS2 promotes ovarian tumor formation by enhancing AKT activity and PD-L1 expression

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