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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,1,10]]},"abstract":"<jats:p>\n                    Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that the circadian clock controls physiological homeostasis of the liver and plays a key role in hepatocarcinogenesis. Despite the progress, cellular and molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing this knowledge gap, we show here that although the human HCC cells Hep3B, HepG2, and Huh7 displayed variations in circadian rhythm profiles, all cells relied on the master circadian clock transcription factors, BMAL1 and CLOCK, for sustained cell growth. Down-regulating\n                    <jats:italic>Bmal1<\/jats:italic>\n                    or\n                    <jats:italic>Clock<\/jats:italic>\n                    in the HCC cells induced apoptosis and arrested cell cycle at the G\n                    <jats:sub>2<\/jats:sub>\n                    \/M phase. Mechanistically, we found that inhibiting\n                    <jats:italic>Bmal1<\/jats:italic>\n                    \/\n                    <jats:italic>Clock<\/jats:italic>\n                    induced dysregulation of the cell cycle regulators\n                    <jats:italic>Wee1<\/jats:italic>\n                    and\n                    <jats:italic>p21<\/jats:italic>\n                    which cooperatively contribute to tumor cell death.\n                    <jats:italic>Bmal1<\/jats:italic>\n                    \/\n                    <jats:italic>Clock<\/jats:italic>\n                    knockdown caused downregulation of\n                    <jats:italic>Wee1<\/jats:italic>\n                    that led to apoptosis activation and upregulation of\n                    <jats:italic>p21<\/jats:italic>\n                    which arrested the cell cycle at the G\n                    <jats:sub>2<\/jats:sub>\n                    \/M phase. Collectively, our results suggest that the circadian clock regulators BMAL1 and CLOCK promote HCC cell proliferation by controlling\n                    <jats:italic>Wee1<\/jats:italic>\n                    and\n                    <jats:italic>p21<\/jats:italic>\n                    levels, thereby preventing apoptosis and cell cycle arrest. Our findings shed light on cellular impact of the clock proteins for maintaining HCC oncogenesis and provide proof-of-principle for developing cancer therapy based on modulation of the circadian clock.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2214829120","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T15:21:36Z","timestamp":1672759296000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":150,"title":["Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle"],"prefix":"10.1073","volume":"120","author":[{"given":"Meng","family":"Qu","sequence":"first","affiliation":[{"name":"International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang 322000, China"},{"name":"Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232"},{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Botany and Plant Sciences, University of California, Riverside, CA 92521"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0597-7518","authenticated-orcid":false,"given":"Alexander","family":"Vu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Wu","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Tsukamoto","sequence":"additional","affiliation":[{"name":"Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Botany and Plant Sciences, University of California, Riverside, CA 92521"},{"name":"Graduate Program in Genetics, Genomics, and Bioinformatics, University of California, Riverside, CA 92521"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3735-9466","authenticated-orcid":false,"given":"Wendong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz-Josef","family":"Lenz","sequence":"additional","affiliation":[{"name":"Division of Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy N.","family":"Rich","sequence":"additional","affiliation":[{"name":"Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232"},{"name":"Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0402-2878","authenticated-orcid":false,"given":"Steve A.","family":"Kay","sequence":"additional","affiliation":[{"name":"Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-0803"},{"key":"e_1_3_4_2_2","article-title":"FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma","volume":"9","author":"C. for D. 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