^2 This was the first production of the Verdi opera in a complete season. ^1 Featuring mayor Henry Kiel as King Richard Microarray data files are deposited in the GEO database (GSE146196).The superscript notes below denote first productions (premieres), world premieres, in-season concerts, etc. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or in the Supplementary Materials. Correspondence and requests for materials should be addressed to H.-Y.W. Competing interests: The authors declare that they have no competing financial interests. guided this project, revised the manuscript, and obtained funding. provided intellectual contributions throughout the project. provided clinical tissue samples and technical guidance. performed xenograft/PDX studies and cell-based assays and helped to analyze data. designed the study, directed the work, and wrote the manuscript. Author contributions: T.-Y.J., L.-W.D., and H.-Y.W. Funding: This work was supported by grants from the State Key Project for Liver Cancer (2017ZX10203206), the National Key Research and Development Program (2017YFC0906900), the National Natural Science Foundation of China (81370066, 81830054, 91859205, 81988101, and 81670516), the Funds for Creative Research Groups of China (81521091), and Shanghai Municipal Commission of Education Project (201901070007E00065). Gough (BioSerendipity LLC, Elkridge, MD). Zhou (Department of Surgery, Eastern Hepatobiliary Surgery Hospital, China) for some cases of PDX model, Hansoh Pharmaceutical Group Company Limited for providing bortezomib, and the Enlighten company for targeting PTEN sequencing. Zou (Tongji Hospital, Huazhong University of Science and Technology, China) for HuCCT1 and TFK1 cell lines, W.-P. You (School of Life Sciences, Xiamen University, China) for SK-CHA-1 and MZ-CHA-1 cell lines, S.-Q. Guo (National Center for Liver Cancer, China) for primary CCA tumor tissue collection, H. Zhao (East China University of Science and Technology, China) for roGFP lentivirus, D. Kopito (Department of Biology, Stanford University) for GFPu plasmid, Y. Ding (National Center for Liver Cancer, China) for AKT-DN adenovirus, R. Chen (National Center for Liver Cancer, China) for revising the manuscript, J. Wang (Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA) and S. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits.

BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research.

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