Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma
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Mario Morales-Martinez1,2, Alberto Valencia-Hipolito1, Gabriel G. Vega1,2, Natividad Neri4, Maria J. Nambo4, Isabel Alvarado5, Ivonne Cuadra5, Marco A. Duran-Padilla6, Otoniel Martinez-Maza7,9, Sara Huerta-Yepez3 and Mario I. Vega1,8
1Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City, México
2Unidad de Posgrado, Facultad de Medicina Universidad Nacional Autónoma de México, México City, México
3Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México “Federico Gómez” S.S.A, México City, México
4Department of Hematology, Oncology Hospital, National Medical Center, IMSS, México City, México
5Servicio de Anatomía Patológica, Hospital de Oncología, Centro Médico Nacional Siglo XXI, IMSS, México City, México
6Servicio de Patología, Hospital General de México “Eduardo Liceaga”, Facultad de Medicina de la UNAM, México City, México
7Department of Obstetrics and Gynecology, Jonsson Comprehensive Cancer Center, UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA
8Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, California, USA
9Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA
Mario I. Vega, email: [email protected]
Keywords: KLF4; hematological malignancies; non-Hodgkin lymphoma; YY1; transcriptional regulation
Abbreviations: B-NHL: B non-Hodgkin lymphoma; DLBCL: diffuse large B cell lymphoma; IHC: immunohistochemistry; KLF: Krüppel-like Factor; YY1: Ying Yang 1
Received: August 20, 2018 Accepted: February 15, 2019 Published: March 15, 2019
Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.
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