Alzahayqa Mahmoud, Jamous Abrar, Khatib Areej A H, Salah Zaidoun
Molecular Genetics Lab, Medicare Laboratories, Ramallah, Palestine.
Department of Molecular Biology and Biochemistry, Al Quds University, Jerusalem, Palestine.
Front Oncol. 2022 May 12;12:848544. doi: 10.3389/fonc.2022.848544. eCollection 2022.
TET1 regulates gene expression by demethylating their regulatory sequences through the conversion of 5-methylcytosine to 5-hyroxymethylcytosine. TET1 plays important roles in tissue homeostasis. In breast cancer, TET1 was shown to play controversial roles. Moreover, TET1 has at least two isoforms (long and short) that have distinct expression pattern and apparently different functions in tissue development and disease including breast cancer. We hypothesized that TET1 isoforms have different expression patterns, localization and regulation in different types of breast cancer. To prove our hypothesis, we studied the expression of TET1 isoforms in basal and luminal breast cancer cell lines, as well as in basal and luminal breast cancer animal models. We also studied the effect of different hormones on the expression of the two isoforms. Moreover, we assessed the distribution of the isoforms between the cytoplasm and nucleus. Finally, we overexpressed the full length in a breast cancer cell line and tested its effect on cancer cell behavior. In this study, we demonstrate that while Estrogen and GnRH downregulate the expression of long TET1, they lead to upregulation of short TET1 expression. In addition, we uncovered that luminal cells show higher expression level of the long isoform. We also show that while all TET1 isoforms are almost depleted in a basal breast cancer animal model, the expression of the short isoform is induced in luminal breast cancer model. The short form is expressed mainly in the cytoplasm while the long isoform is expressed mainly in the nucleus. Finally, we show that long TET1 overexpression suppresses cell oncogenic phenotypes. In conclusion, our data suggest that TET1 isoforms have distinct expression pattern, localization and regulation in breast cancer and that long TET1 suppresses oncogenic phenotypes, and that further studies are necessary to elucidate the functional roles of different TET1 isoforms in breast cancer.
TET1通过将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶来使其调控序列去甲基化，从而调节基因表达。TET1在组织稳态中发挥重要作用。在乳腺癌中，TET1发挥着有争议的作用。此外，TET1至少有两种异构体（长型和短型），它们在包括乳腺癌在内的组织发育和疾病中具有不同的表达模式和明显不同的功能。我们推测TET1异构体在不同类型的乳腺癌中具有不同的表达模式、定位和调控。为了验证我们的推测，我们研究了TET1异构体在基底样和管腔型乳腺癌细胞系以及基底样和管腔型乳腺癌动物模型中的表达。我们还研究了不同激素对这两种异构体表达的影响。此外，我们评估了这两种异构体在细胞质和细胞核之间的分布。最后，我们在一个乳腺癌细胞系中过表达全长TET1，并测试其对癌细胞行为的影响。在本研究中，我们证明雌激素和促性腺激素释放激素下调长型TET1的表达，同时却导致短型TET1表达上调。此外，我们发现管腔型细胞中长异构体的表达水平更高。我们还表明，虽然在基底样乳腺癌动物模型中所有TET1异构体几乎都缺失，但在管腔型乳腺癌模型中短异构体的表达被诱导。短型主要在细胞质中表达，而长型主要在细胞核中表达。最后，我们表明长型TET1过表达抑制细胞致癌表型。总之，我们的数据表明TET1异构体在乳腺癌中具有不同的表达模式、定位和调控，长型TET1抑制致癌表型，并且需要进一步研究以阐明不同TET1异构体在乳腺癌中的功能作用。
