Abstract 3341: Epigenetic deregulation of the Hippo pathway in muscle-derived sarcomas

Soft tissue sarcomas are an aggressive group of roughly 65 mesenchymal malignancies diagnosed in 200,000 people worldwide annually. The treatment approach for sarcomas has not changed significantly in 25 years. Furthermore, recent sequencing efforts have revealed that consistent oncogenic mutations are rare in muscle cancers. As a result, these tumors are not sensitive to most available targeted therapeutics, which specifically interfere with the functions of mutant oncogenic pathways. We are investigating the possibility that together with p53 or RB1 mutation/loss, alterations in chromatin state and epigenetic regulation rather than oncogenic mutation, are required for sarcoma transformation. Based on our current findings we are testing the hypothesis that epigenetic deregulation of Angiomotin (AMOT), a novel tumor suppressor we have identified, is critical for sarcomagenesis. AMOT is highly expressed in differentiated human muscle tissue but is silenced in muscle-derived sarcomas including undifferentiated pleomorphic sarcoma (UPS), a commonly diagnosed and aggressive subtype. Furthermore, ectopic expression of the p130 isoform of AMOT significantly inhibits UPS proliferation. This finding is consistent with the only known function of AMOT in cancer cells, which is to sequester the Hippo pathway effector YAP1 and facilitate its degradation. YAP1 is a pro-proliferation transcriptional activator and deletion of Yap1 in the KrasG12D/+; Trp53fl/fl autochthonous mouse model of UPS. Importantly, treatment of sarcoma cells and tumors with the epigenetic inhibitors SAHA and JQ1 restores p130 AMOT expression, inhibits Yap1, and dramatically reduces sarcomagenesis in vivo. Interestingly, SAHA/JQ1 treatment also induces expression of muscle markers including MYOD and p57 suggesting that epigenetic modulation promotes differentiation as well as inhibiting proliferation. Gene expression studies of control and Yap1-deficient tumors revealed that Yap1 controls NF-κB signaling. We have performed H3K27Ac ChIP-seq and super-enhancer analysis of human UPS tumors to determine whether NF-κB targets are important in human sarcomas. These analyses revealed that NF-κB is the most transcriptionally active pathway in UPS. Together these data suggest that persistent YAP1-mediated NF-κB signaling promotes sarcomagenesis. In normal undifferentiated muscle cells NF-κB signaling is essential for proliferation and inhibition of differentiation. We have now shown that SAHA/JQ1-mediated YAP1 inhibition subsequently decreases NF-κB activity, underscoring the ability of epigenetic therapies to decrease tumorigenesis and enhance differentiation. Our findings suggest that pharmacological modulation of chromatin modifiers will allow us to regain epigenetic control over the Hippo pathway and its downstream targets. Thus we have an opportunity to finally change the treatment paradigm for these patients with novel targeted therapeutics. Note: This abstract was not presented at the meeting. Citation Format: T. S. Karin Eisinger, Shuai Ye. Epigenetic deregulation of the Hippo pathway in muscle-derived sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3341. doi:10.1158/1538-7445.AM2017-3341