@article{d5c706850abd44fbaa708888ccbd6a73,
title = "Cancer-associated exportin-6 upregulation inhibits the transcriptionally repressive and anticancer effects of nuclear profilin-1",
abstract = "Aberrant expression of nuclear transporters and deregulated subcellular localization of their cargo proteins are emerging as drivers and therapeutic targets of cancer. Here, we present evidence that the nuclear exporter exportin-6 and its cargo profilin-1 constitute a functionally important and frequently deregulated axis in cancer. Exportin-6 upregulation occurs in numerous cancer types and is associated with poor patient survival. Reducing exportin-6 level in breast cancer cells triggers antitumor effects by accumulating nuclear profilin-1. Mechanistically, nuclear profilin-1 interacts with eleven-nineteen-leukemia protein (ENL) within the super elongation complex (SEC) and inhibits the ability of the SEC to drive transcription of numerous pro-cancer genes including MYC. XPO6 and MYC are positively correlated across diverse cancer types including breast cancer. Therapeutically, exportin-6 loss sensitizes breast cancer cells to the bromodomain and extra-terminal (BET) inhibitor JQ1. Thus, exportin-6 upregulation is a previously unrecognized cancer driver event by spatially inhibiting nuclear profilin-1 as a tumor suppressor. By defining the moonlighting function of the small actin-binding protein profilin-1 in the nucleus as a transcriptional repressor and the prevalent upregulation of its nuclear exporter exportin-6 in diverse cancer types, Zhu et al. show that deregulation of protein subcellular localization is an important non-oncogene addiction with strong therapeutic potential.",
keywords = "BET bromodomain, ENL, MYC, epigenetics, exportin-6, nucleocytoplasmic transport, profilin-1, super elongation complex, transcription, tumor suppressor",
author = "Cuige Zhu and Kim, {Sun Joong} and Arshag Mooradian and Faliang Wang and Ziqian Li and Sean Holohan and Collins, {Patrick L.} and Keren Wang and Zhanfang Guo and Jeremy Hoog and Ma, {Cynthia X.} and Gene Oltz and Held, {Jason M.} and Jieya Shao",
note = "Funding Information: We thank Dr. Jason Weber and Dr. Brian Van Tine for providing HUMEC and sarcoma cell lines. We thank Dr. Ralph T. Bottcher and Dr. Reinhard Fassler (Max Planck Institute of Biochemistry, Germany) for providing the Pfn1-null mouse chondrocytes. We thank Dr. Shunqiang Li and Tina Primeau for assistance with tumor section. We thank Dr. Kian-Huat Lim for sharing the pSpCas9n(BB)-2A-Puro and LentiCRISPRv2 vectors. We thank Dr. Jingqin Luo for statistical advice. The monoclonal GFP antibody was purchased from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa. We thank the Genome Technology Access Center at Washington University for performing RNA-seq. We thank the Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and the Institute of Clinical and Translational Sciences (ICTS) at Washington University for the use of the Proteomics Shared Resource and the Flow Cytometry core. The Siteman Cancer Center is supported in part by an NCI Cancer Center support grant P30 CA091842, and the ICTS is funded by the National Institutes of Health's NCATS Clinical and Translational Science Award (CTSA) program grant UL1 TR002345. Transcriptomic and proteomic data used in this publication were generated by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium (NCI/NIH). This study was partially supported by the Susan G. Komen Foundation (J.S. CCR14300139), National Cancer Institute (J.S. 5R01CA181671; E.M.O. CA188286), and National Institute of Allergy and Infectious Diseases (E.M.O. AI118852). F.W. was supported by the National Natural Science Foundation of China (81801939). J.S. conceived the project and wrote the manuscript with input from all authors. J.S. C.Z. and S.-J.K. designed the experiments. J.S. C.Z. S.-J.K. F.W. S.H. Z.L. Z.G. and J.M.H. performed the experiments and analyzed the data. A.M. and K.W. performed bioinformatics analysis. J.M.H. C.X.M. P.L.C. and E.M.O. provided technical expertise and intellectual input. No authors declare no competing interests. Funding Information: We thank Dr. Jason Weber and Dr. Brian Van Tine for providing HUMEC and sarcoma cell lines. We thank Dr. Ralph T. Bottcher and Dr. Reinhard Fassler (Max Planck Institute of Biochemistry, Germany) for providing the Pfn1-null mouse chondrocytes. We thank Dr. Shunqiang Li and Tina Primeau for assistance with tumor section. We thank Dr. Kian-Huat Lim for sharing the pSpCas9n(BB)-2A-Puro and LentiCRISPRv2 vectors. We thank Dr. Jingqin Luo for statistical advice. The monoclonal GFP antibody was purchased from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa. We thank the Genome Technology Access Center at Washington University for performing RNA-seq. We thank the Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and the Institute of Clinical and Translational Sciences (ICTS) at Washington University for the use of the Proteomics Shared Resource and the Flow Cytometry core. The Siteman Cancer Center is supported in part by an NCI Cancer Center support grant P30 CA091842 , and the ICTS is funded by the National Institutes of Health {\textquoteright}s NCATS Clinical and Translational Science Award (CTSA) program grant UL1 TR002345 . Transcriptomic and proteomic data used in this publication were generated by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium (NCI/NIH). This study was partially supported by the Susan G. Komen Foundation (J.S., CCR14300139 ), National Cancer Institute (J.S., 5R01CA181671 ; E.M.O., CA188286 ), and National Institute of Allergy and Infectious Diseases (E.M.O., AI118852 ). F.W. was supported by the National Natural Science Foundation of China ( 81801939 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = feb,
day = "16",
doi = "10.1016/j.celrep.2021.108749",
language = "English",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
number = "7",
}