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Supplementary Figure 1 from Loss of Rassf1a Synergizes with Deregulated Runx2 Signaling in Tumorigenesis

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posted on 2023-03-30, 21:16 authored by Louise van der Weyden, Angelos Papaspyropoulos, George Poulogiannis, Alistair G. Rust, Mamunur Rashid, David J. Adams, Mark J. Arends, Eric O'Neill

PDF file - 64K, U2OS cells were transfected with either non-targeting (NT) or siRNA RUNX2 as above, in the presence or absence of siRNA targeting RASSF1A, and endogenous YAP1 immunoprecipitates were blotted with the indicated antibodies

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ARTICLE ABSTRACT

The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a-null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A-mediated tumor suppression. Cancer Res; 72(15); 3817–27. ©2012 AACR.