Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma.
Multiple myeloma is a hematological cancer of plasma B cells and remains incurable. Two major subtypes of myeloma, hyperdiploid MM (HMM) and non-hyperdiploid MM (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis, but their dysregulation in myeloma subtypes are less studied. Here, we developed a TrF-pathway coexpression analysis to identify altered coexpression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, nuclear factor-κB and HOXA9 have significantly lower coexpression with cell cycle arrest in HMM, co-occurring with their overactivation in HMM. In contrast, TrFs ESR1 (estrogen receptor 1), SP1 and E2F1 have significantly lower coexpression with cell cycle arrest in NHMM. SP1 chromatin immunoprecipitation targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their overactivation in NHMM disrupts proper regulation of cell cycle arrest. Cotargeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway coexpression dysregulation in human cancers facilitates forming novel hypotheses toward clinical utility.
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
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Wang
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
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Yan
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, VA Boston Healthcare System, Boston, MA, USA.
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Fulciniti
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
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Li
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, VA Boston Healthcare System, Boston, MA, USA.
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Gkotzamanidou
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
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Amin
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
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Shah
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
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Zhang
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, VA Boston Healthcare System, Boston, MA, USA.
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Munshi
1] Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China [2] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA, USA.
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Li
D001499:Bayes Theorem; D059447:Cell Cycle Checkpoints; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D050687:E2F1 Transcription Factor / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D020935:MAP Kinase Signaling System; D009101:Multiple Myeloma / Q000473:pathology*; D016329:Sp1 Transcription Factor / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018398:Homeodomain Proteins; D015850:Interleukin-6; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2