Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma

// Mario Morales-Martinez 1, 2 , Alberto Valencia-Hipolito 1 , Gabriel G. Vega 1, 2 , Natividad Neri 4 , Maria J. Nambo 4 , Isabel Alvarado 5 , Ivonne Cuadra 5 , Marco A. Duran-Padilla 6 , Otoniel Martinez-Maza 7, 9 , Sara Huerta-Yepez 3 and Mario I. Vega 1, 8 1 Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, Mexico City, Mexico 2 Unidad de Posgrado, Facultad de Medicina Universidad Nacional Autonoma de Mexico, Mexico City, Mexico 3 Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico “Federico Gomez” S.S.A, Mexico City, Mexico 4 Department of Hematology, Oncology Hospital, National Medical Center, IMSS, Mexico City, Mexico 5 Servicio de Anatomia Patologica, Hospital de Oncologia, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico 6 Servicio de Patologia, Hospital General de Mexico “Eduardo Liceaga”, Facultad de Medicina de la UNAM, Mexico City, Mexico 7 Department of Obstetrics and Gynecology, Jonsson Comprehensive Cancer Center, UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, California, USA 8 Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, California, USA 9 Department 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 Correspondence to: Mario I. Vega, email: marioi@unam.mx 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: Kruppel-like Factor; YY1: Ying Yang 1 Received: August 20, 2018      Accepted: February 15, 2019      Published: March 15, 2019 ABSTRACT Kruppel-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.