YAP1 enhances NF-κB-dependent and independent effects on clock-mediated unfolded protein responses and autophagy in sarcoma

Abstract

Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle, and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is partially contingent upon downregulation of the Hippo pathway transcriptional effector Yes-associated protein 1 (YAP1) and nuclear factor (NF)-κB. Previously, we observed that Vorinostat/JQ1 inactivates YAP1 and restores oscillation of NF-κB in differentiating myoblasts. These effects correlate with reduced tumorigenesis, and enhanced differentiation. However, the mechanisms by which the Hippo/NF-κB axis impact differentiation remained unknown. Here, we report that YAP1 and NF-κB activity suppress circadian clock function, inhibiting differentiation and promoting proliferation. In most tissues, clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR activity, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS, we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via inhibition of YAP1/NF-κB. These findings support the use of epigenetic modulators to treat human UPS. In addition, we identify specific autophagy, UPR, and muscle differentiation-associated genes as potential biomarkers of treatment efficacy and differentiation.

H3K27ac‐activated LINC00519 promotes lung squamous cell carcinoma progression by targeting miR‐450b‐5p/miR‐515‐5p/YAP1 axis

“…YAP1 is an essential downstream gene of Hippo pathway and has been reported as a carcinogen in cancers. For instance, YAP1 promotes the autophagy in sarcoma 39. YAP1 is reported to be overexpressed in thyroid papillary carcinoma 40.…”

TGFβ and Hippo Pathways Cooperate to Enhance Sarcomagenesis and Metastasis through the Hyaluronan-Mediated Motility Receptor (HMMR)

“…However, we observed that the combination of these drugs is by far the most effective pharmacologic method for inhibiting YAP1 expression and activity. Importantly, SAHA/JQ1 treatment does not trigger cell death, but rather induces differentiation in sarcoma cells (5,43). Although SAHA/JQ1 treatment has pleotropic effects, we use these tools to interrogate and then validate YAP1-mediated signaling and related phenotypes.…”

Glycyrrhizin Attenuates Carcinogenesis by Inhibiting the Inflammatory Response in a Murine Model of Colorectal Cancer

“…We have previously reported that increased DNA damage due to inflammation may result in the mutation of stem cells, leading to tumor development [ 54 ]. It has been reported that NF-κB is activated by YAP1 [ 55 , 56 ]. To determine whether CSCs involved in inflammation can also cause tumor development, we examined the expression of stem cell markers YAP1 and SOX9, and found that their expression in the cancer cells in the CC group was significantly higher than that in the normal cells of the control group.…”