LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis.

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.