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Myo-differentiation reporter screen reveals NF-Y as an activator of PAX3-FOXO1 in rhabdomyosarcoma.
Sroka, Martyna W; Skopelitis, Damianos; Vermunt, Marit W; Preall, Jonathan B; El Demerdash, Osama; de Almeida, Larissa M N; Chang, Kenneth; Utama, Raditya; Gryder, Berkley; Caligiuri, Giuseppina; Ren, Diqiu; Nalbant, Benan; Milazzo, Joseph P; Tuveson, David A; Dobin, Alexander; Hiebert, Scott W; Stengel, Kristy R; Mantovani, Roberto; Khan, Javed; Kohli, Rahul M; Shi, Junwei; Blobel, Gerd A; Vakoc, Christopher R.
Afiliação
  • Sroka MW; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Skopelitis D; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Vermunt MW; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  • Preall JB; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • El Demerdash O; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • de Almeida LMN; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Chang K; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Utama R; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Gryder B; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106.
  • Caligiuri G; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Ren D; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • Nalbant B; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Milazzo JP; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Tuveson DA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Dobin A; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
  • Hiebert SW; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
  • Stengel KR; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461.
  • Mantovani R; Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
  • Khan J; Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892.
  • Kohli RM; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104.
  • Shi J; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
  • Blobel GA; Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  • Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
Proc Natl Acad Sci U S A ; 120(36): e2303859120, 2023 09 05.
Article em En | MEDLINE | ID: mdl-37639593
Recurrent chromosomal rearrangements found in rhabdomyosarcoma (RMS) produce the PAX3-FOXO1 fusion protein, which is an oncogenic driver and a dependency in this disease. One important function of PAX3-FOXO1 is to arrest myogenic differentiation, which is linked to the ability of RMS cells to gain an unlimited proliferation potential. Here, we developed a phenotypic screening strategy for identifying factors that collaborate with PAX3-FOXO1 to block myo-differentiation in RMS. Unlike most genes evaluated in our screen, we found that loss of any of the three subunits of the Nuclear Factor Y (NF-Y) complex leads to a myo-differentiation phenotype that resembles the effect of inactivating PAX3-FOXO1. While the transcriptomes of NF-Y- and PAX3-FOXO1-deficient RMS cells bear remarkable similarity to one another, we found that these two transcription factors occupy nonoverlapping sites along the genome: NF-Y preferentially occupies promoters, whereas PAX3-FOXO1 primarily binds to distal enhancers. By integrating multiple functional approaches, we map the PAX3 promoter as the point of intersection between these two regulators. We show that NF-Y occupies CCAAT motifs present upstream of PAX3 to function as a transcriptional activator of PAX3-FOXO1 expression in RMS. These findings reveal a critical upstream role of NF-Y in the oncogenic PAX3-FOXO1 pathway, highlighting how a broadly essential transcription factor can perform tumor-specific roles in governing cellular state.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Rabdomiossarcoma Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Rabdomiossarcoma Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article