The downregulation of putative anticancer target BORIS/CTCFL in an addicted myeloid cancer cell line modulates the expression of multiple protein coding and ncRNA genes

Evgeny Teplyakov,Abdelhalim Boukaba,Alexander Strunnikov,Qiongfang Wu,Jian Liu,Elena M Pugacheva,Dmitry Loukinov,Victor Lobanenkov

doi:10.18632/oncotarget.20627

Abstract

The BORIS/CTCFL gene, is a testis-specific CTCF paralog frequently erroneously activated in cancer, although its exact role in cancer remains unclear. BORIS is both a transcription factor and an architectural chromatin protein. BORIS’ normal role is to establish a germline-like gene expression and remodel the epigenetic landscape in testis; it similarly remodels chromatin when activated in human cancer. Critically, at least one cancer cell line, K562, is dependent on BORIS for its self-renewal and survival.Here, we downregulate BORIS expression in the K562 cancer cell line to investigate downstream pathways regulated by BORIS. RNA-seq analyses of both mRNA and small ncRNAs, including miRNA and piRNA, in the knock-down cells revealed a set of differentially expressed genes and pathways, including both testis-specific and general proliferation factors, as well as proteins involved in transcription regulation and cell physiology. The differentially expressed genes included important transcriptional regulators such as SOX6 and LIN28A. Data indicate that both direct binding of BORIS to promoter regions and locus-control activity via long-distance chromatin domain regulation are involved. The sum of findings suggests that BORIS activation in leukemia does not just recapitulate the germline, but creates a unique regulatory network.

Highlights

Cancer-testis antigens are immunogenic proteins normally restricted to expression in the male germline but are frequently activated in various types of cancer [1,2,3,4]
With respect to gene regulation, both repression and activation could be potentially handled by BORIS, as we previously showed that it can act as either an activator or repressor of transcription, dependent on the particular gene [33, 36]
Three independent experiments were used, with K562 cells stably infected by the corresponding empty lentivirus vector (EV) and induced by doxycycline

Summary

Introduction

Cancer-testis antigens are immunogenic proteins normally restricted to expression in the male germline but are frequently activated in various types of cancer [1,2,3,4]. It was documented that cancer cells expressing high level of BORIS tend to display a characteristic pattern of BORIS binding to chromosomal locations, which is largely independent of the cancer cell origin, but instead recapitulates the binding landscape in male germ cells [33, 35]. Consistent with this interpretation, the ectopic expression of BORIS in MCF7 cells induced notable changes in the expression level of corresponding genes and recapitulated the germ cell pattern of BORIS binding

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Results

Conclusion