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Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth

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Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth Published OnlineFirst October 23, 2017; DOI: 10.1158/1541-7786.MCR-17-0382 Signal Transduction Molecular Cancer Research Novel YAP1 Activator, Identified by Transcription- Based Functional Screen, Limits Multiple Myeloma Growth Junichi Maruyama1, Kazutoshi Inami1, Fumiyoshi Michishita1, Xinliang Jiang1, Hiroaki Iwasa1, Kentaro Nakagawa1, Mari Ishigami-Yuasa2, Hiroyuki Kagechika2,3, Norio Miyamura4, Jun Hirayama4, Hiroshi Nishina4, Daichi Nogawa5, Kouhei Yamamoto5, and Yutaka Hata1,6 Abstract Yes-associated protein 1 (YAP1) interacts with numerous this in our mind, we screened for YAP1 activators by using transcription factors, including TEA-domain family proteins human retinal pigment epithelial ARPE-19 cells expressing the (TEAD) and p73. YAP1 is negatively regulated by the tumor TEAD-responsive fluorescence reporter under the coexpression suppressor Hippo pathway. In human cancers, the deregulation of YAP1. From an extensive chemical compound library (n ¼ of the Hippo pathway and YAP1 gene amplification lead to the 18,606) 47 candidate YAP1 activators were identified. These activation of YAP1, which induces epithelial–mesenchymal compounds were characterized to determine whether this assay transition (EMT) and drug resistance. YAP1 inhibitors are provides bona fide YAP1 activators. Importantly, one YAP1 expected to be useful in cancer therapy. On the other hand, activator was effective against the human multiple myeloma in certain cancers, YAP1 upregulates p73-dependent gene tran- IM-9 cells and chronic myeloid leukemia K562 cells. scription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem Implications: YAP1 activation limits growth, induces apoptosis, cells and plays an important role in tissue homeostasis, YAP1 and may be useful at suppressing hematological cancers. activators may contribute to the regenerative medicine. With Mol Cancer Res; 1–15. Ó2017 AACR. Introduction to the cytoplasm and undergoes degradation. In human cancers, the Hippo pathway is frequently deregulated and the YAP1 gene is Yes-associated protein 1 (YAP1) was identified as a protein amplified, so that YAP1 activity is enhanced (9). YAP1 upregulates interacting with yes tyrosine kinase (1). Thereafter, many YAP1- cell cycle–promoting and antiapoptotic genes (10). Cancer cells interacting proteins, such as ErbB4, p73, TEAD, SMAD, and with hyperactive YAP1 undergo epithelial–mesenchymal transi- Runx2, were reported (2–6). YAP1 does not directly bind to DNA tion and acquire drug resistance (10). The activity of YAP1 but regulates gene transcription through the interaction with these correlates with short survival in cancer patients. Hence, YAP1 is molecules. YAP1 is negatively regulated by the tumor suppressor regarded as a therapeutic target in cancer therapy (11). Among Hippo pathway (7, 8). YAP1 is phosphorylated by large tumor transcription factors interacting with YAP1, TEAD is the most suppressor kinase (LATS) 1 and 2, the core kinases of the Hippo important in the induction of epithelial–mesenchymal transition pathway. The phosphorylated YAP1 is recruited from the nucleus and drug resistance (12, 13). Accordingly, verteporfin and syn- thetic peptides that block the interaction between YAP1 and TEAD are shown to suppress cancer growth (14–16). 1Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. 2Chemical Biology The role of YAP1 in cancer is twisting. YAP1 cooperates with Screening Center, Tokyo Medical and Dental University, Tokyo, Japan. 3Institute p73, upregulates proapoptotic genes, and suppresses certain of Biomaterials and Bioengineering, Tokyo Medical and Dental University, cancers (17). How YAP1 determines which fate as an oncopro- Tokyo, Japan. 4Department of Developmental and Regenerative Biology, Med- tein or as a tumor suppressor to adopt is not fully understood, ical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. but the accumulating evidence suggests that Abelson murine 5Department of Comprehensive Pathology, Graduate School of Medical and leukemia viral oncogene homolog 1 (ABL1) is a key determi- Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. 6Center for Brain Integration Research, Tokyo Medical and Dental University, Tokyo, Japan. nant (18). Upon DNA damage, ABL1 phosphorylates YAP1 at tyrosine 357 and promotes the interaction with p73. A recent Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). study has revealed that multiple myeloma (MM) cells show DNA damage response but escape cell death, because YAP1 J. Maruyama, K. Inami, and F. Michishita contributed equally to this article. activity is low (19). When YAP1 is exogenously expressed or the Corresponding Author: Yutaka Hata, Tokyo Medical and Dental University, 1-5- Hippo pathway is suppressed to enhance YAP1 expression, MM 45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81358035164; Fax: cells die via the ABL1–YAP1–p73 axis. We can surmise that in 81358030121; E-mail: [email protected] cancers with the high expression of ABL1 and with the low doi: 10.1158/1541-7786.MCR-17-0382 expression of YAP1, YAP1 activators trigger apoptosis and are Ó2017 American Association for Cancer Research. therapeutically effective. www.aacrjournals.org OF1 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst October 23, 2017; DOI: 10.1158/1541-7786.MCR-17-0382 Maruyama et al. YAP1 plays a crucial role in the regulation of tissue stem cells from H2B-mCherry (a gift from Robert Benezra; Addgene (20). YAP1 is essential for tissue repair and protection in intestine, plasmid, 20972; ref. 34) were ligated into NotI/XbaI sites liver, heart, and skin (21–26). YAP1 is also necessary to maintain of pLL3.7 K122 FH-YAP1 and pLL3.7 K122 to obtain neural stem cells in the brain (27). Based on these properties of pLL3.7 K122 FH-YAP1-ires-GFP-TEAD-responsive-promoter- YAP1, we infer that YAP1 activators are useful in the regenerative H2B-mCherry reporter (Fig. 1A) and pLL3.7 K122 control- medicine. TEAD-responsive-promoter-H2B-mCherry, respectively. pCMV We previously searched for YAP1 modulators by means of FLAG-human YAP1 was described previously (35). pCIneoMyc- human osteosarcoma U2OS cells expressing green fluorescent and pCIneoFLAG-LATS1 were generated from pCGN HA-Warts protein (GFP)-tagged YAP1 (28). We used the subcellular (a gift from Hiroyuki Saya) using PCR with the primers (H1921, localization of GFP-YAP1 as the readout and found that 50-acgcgtatgaggcctaagacctttcc-30 and H1922, 50-gtcgactaaacatatac- dobutamine inhibits YAP1 through b-adrenergic receptor. tagatcgcga-30), while pCIneoMyc-LATS2 was generated from However, we have not yet found the compounds that activate pcDNA LATS2-FLAG (a gift from Tadashi Yamamoto) YAP1. In this study, we established a new cell-based assay, in with the primers (H1923, 50-acgcgtatgaggccaaagacttttcc-30 and which the YAP1-dependent TEAD-responsive reporter activity H1924, 50-gtcgactacacgtacacaggctggc-30). pCIneoLuc-PP1A and is monitored. We performed a small chemical compound pCIneoLuc-PP2A were described previously (30). pCMV SPORT library screening with the use of this assay and obtained human TEAD4 (MHS1010-58163) was purchased from Open candidate YAP1 activators. We characterized these compounds Biosystems. PCR was performed with the primers (H2710, to examine whether they indeed activate YAP1 and tested the 50-gaattcgagggcacggccggcaccat-30 and H2710, 50-gtcgactcattcttt- idea that YAP1 activator can be used against MM and other caccagcctg-30). The PCR product was ligated into EcoRI/Sall sites blood cancer cells. of pCIneoLuc to generate pCIneoLuc-TEAD4. pCMV alkaline phosphatase is a gift from Sumiko Watanabe. PCR was performed with the primers (H3159, 50-gcggccgcttaagtgaacaactagtgcca-30 and Materials and Methods H3160, 50-caattgagatctttcacaaattttgtaatc-30) on piLenti-siRNA- DNA constructions and virus productions GFP (Applied Biological Materials Inc.) to amplify GFP-2A-puro- pCIneoFLAG-His6 (pCIneoFH), pClneoFLAG-His6-FLAG mycin. The product was digested with SpeI/MfeI and ligated into (pClneoFHF), pCIneoMyc, pCIneoLuc, pCIneomCherry, and NheI/EcoRI of pLL3.7 to generate pLL3.7-GFP-2A-puro. PCR was pQCXIP-EF were described previously (28–32). NheI/EcoRI frag- performed with the primers (H3161, 50-gcggccgcccccttcacc- ment was isolated from pEGFP-C2 (Clontech Laboratories) and gagggcctattt-30 and H3162, agatctagactattctttcccctgcactgt-30)on ligated into NheI/EcoRI sites of pCIneo (Promega) to generate pLKO1-shYAP2 (a gift from Kunliang Guan; Addgene plasmid, pCIneoEGFPC2. pIRES2-EGFP (Clontech Laboratories) was cut 27369; ref. 6). The product was digested with NotI/XbaI and with NotI, filled in, and digested with NheI. pLL3.7 vector was ligated into the same sites of pLL3.7-GFP-2A-shYAP2. Human cut with EcoRI, filled in, and digested with NheI. The fragment p73 cDNA was obtained from Open Biosystem (40125802). from pIRES-EGFP was ligated into pLL3.7 to replace GFP with The coding region was amplified by PCR with the primers IRES-GFP and the resulting vector was named pLL3.7 K122. PCR (H2074, 50-acgcgtatggcccagtccaccgccac-30 and H2075, 50-gtcgact- 0 was performed with the primers (H3244, 5 -caattggcagaaatcgg- cagtggatctcggcctcc-30), digested by MluI/Sall, and ligated 0 0 tactggctttccatc-3 and H3245, 5 -acgcgtgaattccgcgttatcgctct-
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