PMID- 36180487 OWN - NLM STAT- MEDLINE DCOM- 20221004 LR - 20240130 IS - 2041-4889 (Electronic) VI - 13 IP - 10 DP - 2022 Oct 1 TI - PAF1 cooperates with YAP1 in metaplastic ducts to promote pancreatic cancer. PG - 839 LID - 10.1038/s41419-022-05258-x [doi] LID - 839 AB - Acinar-to-ductal metaplasia (ADM) is a precursor lesion of pancreatic ductal adenocarcinoma (PDAC); however, the regulators of the ADM-mediated PDAC development and its targeting are poorly understood. RNA polymerase II-associated factor 1 (PAF1) maintains cancer stem cells leading to the aggressiveness of PDAC. In this study, we investigated whether PAF1 is required for the YAP1-mediated PDAC development and whether CA3 and verteporfin, small molecule inhibitors of YAP1/TEAD transcriptional activity, diminish pancreatic cancer (PC) cell growth by targeting the PAF1/YAP1 axis. Here, we demonstrated that PAF1 co-expresses and interacts with YAP1 specifically in metaplastic ducts of mouse cerulein- or Kras(G12D)-induced ADM and human PDAC but not in the normal pancreas. PAF1 knockdown (KD) reduced SOX9 in PC cells, and the PC cells showed elevated PAF1/YAP1 complex recruitment to the promoter of SOX9. The PAF1 KD reduced the 8xTEAD and SOX9 promoter-luciferase reporter activities in the mouse KC (Kras(G12D); Pdx-1 Cre) cells and human PC cells, indicating that the PAF1 is required for the YAP1-mediated development of ADM and PC. Moreover, treatment with CA3 or verteporfin reduced the expressions of PAF1, YAP1, TEAD4, and SOX9 and decreased colony formation and stemness in KC and PC cells. CA3 treatment also reduced the viability and proliferation of PC cells and diminished the duct-like structures in KC acinar explants. CA3 or verteporfin treatment decreased the recruitment of the PAF1/YAP1 complex to the SOX9 promoter in PC cells and reduced the 8xTEAD and SOX9 promoter-luciferase reporter activities in KC and PC cells. Overall, PAF1 cooperates with YAP1 during ADM and PC development, and verteporfin and CA3 inhibit ADM and PC cell growth by targeting the PAF1/YAP1/SOX9 axis in vitro and ex vivo models. This study identified a regulatory axis of PDAC initiation and its targeting, paving the way for developing targeted therapeutic strategies for pancreatic cancer patients. CI - (c) 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Nimmakayala, Rama Krishna AU - Nimmakayala RK AUID- ORCID: 0000-0003-4637-4828 AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Ogunleye, Ayoola O AU - Ogunleye AO AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Parte, Seema AU - Parte S AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Krishna Kumar, Nivedeta AU - Krishna Kumar N AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Raut, Pratima AU - Raut P AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Varadharaj, Venkatesh AU - Varadharaj V AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Perumal, Naveen Kumar AU - Perumal NK AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Nallasamy, Palanisamy AU - Nallasamy P AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Rauth, Sanchita AU - Rauth S AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. FAU - Cox, Jesse L AU - Cox JL AD - Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Lele, Subodh M AU - Lele SM AD - Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA. FAU - Batra, Surinder K AU - Batra SK AUID- ORCID: 0000-0001-9470-9317 AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. sbatra@unmc.edu. AD - Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. sbatra@unmc.edu. FAU - Ponnusamy, Moorthy P AU - Ponnusamy MP AUID- ORCID: 0000-0001-5744-193X AD - Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA. mpalanim@unmc.edu. AD - Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. mpalanim@unmc.edu. LA - eng GR - R01 CA263575/CA/NCI NIH HHS/United States GR - R01 CA256973/CA/NCI NIH HHS/United States GR - R01 CA273349/CA/NCI NIH HHS/United States GR - U01 CA210240/CA/NCI NIH HHS/United States GR - R01 CA210637/CA/NCI NIH HHS/United States GR - P01 CA217798/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221001 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (DNA-Binding Proteins) RN - 0 (PAF1 protein, human) RN - 0 (TEA Domain Transcription Factors) RN - 0 (TEAD4 protein, human) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 0X9PA28K43 (Verteporfin) RN - 888Y08971B (Ceruletide) RN - EC 1.13.12.- (Luciferases) RN - EC 2.7.7.- (RNA Polymerase II) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Acinar Cells/metabolism MH - Animals MH - *Carcinoma, Pancreatic Ductal/pathology MH - Cell Transformation, Neoplastic/genetics MH - Ceruletide MH - DNA-Binding Proteins/metabolism MH - Humans MH - Luciferases/metabolism MH - Metaplasia/metabolism/pathology MH - Mice MH - Pancreatic Ducts/pathology MH - *Pancreatic Neoplasms/pathology MH - Proto-Oncogene Proteins p21(ras)/metabolism MH - RNA Polymerase II/metabolism MH - TEA Domain Transcription Factors MH - Transcription Factors MH - Verteporfin/pharmacology MH - YAP-Signaling Proteins PMC - PMC9525575 COIS- SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The remaining authors declare no competing interests. EDAT- 2022/10/01 06:00 MHDA- 2022/10/05 06:00 PMCR- 2022/10/01 CRDT- 2022/09/30 23:21 PHST- 2022/05/10 00:00 [received] PHST- 2022/09/12 00:00 [accepted] PHST- 2022/09/09 00:00 [revised] PHST- 2022/09/30 23:21 [entrez] PHST- 2022/10/01 06:00 [pubmed] PHST- 2022/10/05 06:00 [medline] PHST- 2022/10/01 00:00 [pmc-release] AID - 10.1038/s41419-022-05258-x [pii] AID - 5258 [pii] AID - 10.1038/s41419-022-05258-x [doi] PST - epublish SO - Cell Death Dis. 2022 Oct 1;13(10):839. doi: 10.1038/s41419-022-05258-x.