Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
PLoS One. 2012;7(7):e40389. doi: 10.1371/journal.pone.0040389. Epub 2012 Jul 5.
Testis-specific transcription factor BORIS (Brother of the Regulator of Imprinted Sites), a paralog and proposed functional antagonist of the widely expressed CTCF, is abnormally expressed in multiple tumor types and has been implicated in the epigenetic activation of cancer-testis antigens (CTAs). We have reported previously that suprabasin (SBSN), whose expression is restricted to the epidermis, is epigenetically derepressed in lung cancer. In this work, we establish that SBSN is a novel non-CTA target of BORIS epigenetic regulation. With the use of a doxycycline-inducible BORIS expressing vector, we demonstrate that relative BORIS dosage is critical for SBSN activation. At lower concentrations, BORIS induces demethylation of the SBSN CpG island and disruption and activation of chromatin around the SBSN transcription start site (TSS), resulting in a 35-fold increase in SBSN expression in the H358 human lung cancer cell line. Interestingly, increasing BORIS concentrations leads to a subsequent reduction in SBSN expression via chromatin repression. In a similar manner, increase in BORIS concentrations leads to eventual decrease of cell growth and colony formation. This is the first report demonstrating that different amount of BORIS defines its varied effects on the expression of a target gene via chromatin structure reorganization.
睾丸特异性转录因子 BORIS（印迹位点调节因子的兄弟）是一种与广泛表达的 CTCF 具有同源性的蛋白，被认为是其功能拮抗物，其在多种肿瘤类型中异常表达，并与癌症睾丸抗原（CTAs）的表观遗传激活有关。我们之前曾报道过，超basin（SBSN）的表达局限于表皮，在肺癌中其表观遗传被去抑制。在这项工作中，我们确定 SBSN 是 BORIS 表观遗传调控的一个新的非 CTA 靶标。通过使用可诱导表达 BORIS 的四环素诱导载体，我们证明了相对 BORIS 剂量对 SBSN 的激活至关重要。在较低浓度下，BORIS 诱导 SBSN CpG 岛去甲基化，并破坏和激活 SBSN 转录起始位点（TSS）周围的染色质，导致 H358 人肺癌细胞系中 SBSN 表达增加 35 倍。有趣的是，增加 BORIS 浓度会导致 SBSN 表达的后续减少，这是通过染色质抑制实现的。以类似的方式，增加 BORIS 浓度会导致细胞生长和集落形成的最终减少。这是第一个报道，证明不同量的 BORIS 通过染色质结构重排定义了其对靶基因表达的不同影响。
