Role of the Transcription Factor Yin Yang 1 and Its Selectively Identified Target Survivin in High-Grade B-Cells Non-Hodgkin Lymphomas: Potential Diagnostic and Therapeutic Targets.

Gaetano Giuseppe Magro,Silvia Vivarelli,Adriana Garozzo,Giovanni Ligresti,Luca Falzone,Saverio Candido,Benjamin Bonavida,Massimo Libra

doi:10.3390/ijms21176446

Abstract

B-cell non-Hodgkin lymphomas (B-NHLs) are often characterized by the development of resistance to chemotherapeutic drugs and/or relapse. During drug-induced apoptosis, Yin Yang 1 (YY1) transcription factor might modulate the expression of apoptotic regulators genes. The present study was aimed to: (1) examine the potential oncogenic role of YY1 in reversing drug resistance in B-NHLs; and (2) identify YY1 transcriptional target(s) that regulate the apoptotic pathway in B-NHLs. Predictive analyses coupled with database-deposited data suggested that YY1 binds the promoter of the BIRC5/survivin anti-apoptotic gene. Gene Expression Omnibus (GEO) analyses of several B-NHL repositories revealed a conserved positive correlation between YY1 and survivin, both highly expressed, especially in aggressive B-NHLs. Further validation experiments performed in Raji Burkitt’s lymphomas cells, demonstrated that YY1 silencing was associated with survivin downregulation and sensitized the cells to apoptosis. Overall, our results revealed that: (1) YY1 and survivin are positively correlated and overexpressed in B-NHLs, especially in BLs; (2) YY1 strongly binds to the survivin promoter, hence survivin may be suggested as YY1 transcriptional target; (3) YY1 silencing sensitizes Raji cells to drug-induced apoptosis via downregulation of survivin; (4) both YY1 and survivin are potential diagnostic markers and therapeutic targets for the treatment of resistant/relapsed B-NHLs.

Highlights

Worldwide, non-Hodgkin lymphomas (NHLs) represent the tenth most frequent cancers in males and the twelfth most diffused tumors in females, respectively, with an estimation of 509,590 new cases and 248,724 deaths in the past 2018, according to The Global Cancer Observatory (GLOBOCAN) of the World Health Organization (WHO) [1]
Recent studies suggested that Yin Yang 1 (YY1) negatively regulates apoptosis in B-cells non-Hodgkin’s Lymphoma (B-NHL) cells, promoting pro-survival programs and, in turn, resistance to cytotoxic stimuli
To identify the potential direct transcriptional targets of YY1 in B-NHLs, JASPAR in-silico analysis was performed to search for the presence of YY1 putative binding sites located within the transcriptional regulatory region of the main genes involved in the modulation of the apoptosis, including the B-cell lymphoma 2 (BCL2) family members, as well as inhibitors of apoptosis proteins (IAPs) members

Summary

Introduction

Non-Hodgkin lymphomas (NHLs) represent the tenth most frequent cancers in males and the twelfth most diffused tumors in females, respectively, with an estimation of 509,590 new cases and 248,724 deaths in the past 2018, according to The Global Cancer Observatory (GLOBOCAN) of the World Health Organization (WHO) [1]. This group of tumors stems from the malignant transformation of mature and immature cells of the immune system, affecting either B lymphocytes (B cells, representing around 86% of all NHLs), and T- and natural killer (NK) cells (14% of all NHLs) [1]. YY1 positively or negatively regulates the expression of target genes directly, by binding a conserved 12-mer consensus sequence located within the DNA transcriptional regulatory region, or indirectly, following the interaction either with other transcription factors or with co-activators/co-repressors of the transcription, as well as general epigenetic modulators [6]

Objectives

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Results