Finotti Alessia, Gasparello Jessica, Zuccato Cristina, Cosenza Lucia Carmela, Fabbri Enrica, Bianchi Nicoletta, Gambari Roberto
Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, 44121 Ferrara, Italy.
Department of Translational Medicine and for Romagna, Ferrara University, 44121 Ferrara, Italy.
Genes (Basel). 2023 Oct 11;14(10):1927. doi: 10.3390/genes14101927.
The anticancer drug mithramycin (MTH), has been proposed for drug repurposing after the finding that it is a potent inducer of fetal hemoglobin (HbF) production in erythroid precursor cells (ErPCs) from β-thalassemia patients. In this respect, previously published studies indicate that MTH is very active in inducing increased expression of γ-globin genes in erythroid cells. This is clinically relevant, as it is firmly established that HbF induction is a valuable approach for the therapy of β-thalassemia and for ameliorating the clinical parameters of sickle-cell disease (SCD). Therefore, the identification of MTH biochemical/molecular targets is of great interest. This study is inspired by recent robust evidence indicating that the expression of γ-globin genes is controlled in adult erythroid cells by different transcriptional repressors, including Oct4, MYB, BCL11A, Sp1, KLF3 and others. Among these, BCL11A is very important. In the present paper we report evidence indicating that alterations of BCL11A gene expression and biological functions occur during MTH-mediated erythroid differentiation. Our study demonstrates that one of the mechanisms of action of MTH is a down-regulation of the transcription of the BCL11A gene, while a second mechanism of action is the inhibition of the molecular interactions between the BCL11A complex and specific sequences of the γ-globin gene promoter.
抗癌药物光辉霉素（mithramycin，MTH），在被发现是β地中海贫血患者红系前体细胞（ErPCs）中胎儿血红蛋白（HbF）产生的强效诱导剂后，已被提议用于药物再利用。在这方面，先前发表的研究表明，MTH在诱导红系细胞中γ珠蛋白基因表达增加方面非常活跃。这具有临床相关性，因为HbF诱导是治疗β地中海贫血和改善镰状细胞病（SCD）临床参数的一种有价值的方法这一点已得到确凿证实。因此，确定MTH的生化/分子靶点非常重要。本研究受到最近有力证据的启发，这些证据表明，γ珠蛋白基因的表达在成年红系细胞中受不同转录抑制因子控制，包括Oct4、MYB、BCL11A、Sp1、KLF3等。其中，BCL11A非常重要。在本文中，我们报告了表明在MTH介导的红系分化过程中BCL11A基因表达和生物学功能发生改变的证据。我们的研究表明，MTH的作用机制之一是下调BCL11A基因的转录，而另一个作用机制是抑制BCL11A复合物与γ珠蛋白基因启动子特定序列之间的分子相互作用。
