Institute of Human Genetics, Jena University Hospital, Jena, Germany.
Institute of Human Genetics, Jena University Hospital, Jena, Germany; Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
J Steroid Biochem Mol Biol. 2020 Jul;201:105689. doi: 10.1016/j.jsbmb.2020.105689. Epub 2020 May 1.
While several studies link a state of hypothyroidism to extended lifespan of humans and mice, the role of thyroid hormone in cancer is more controversial since tumor-promoting as well as tumor-suppressive effects are known. In general, aberrant thyroid hormone levels are associated with increased cancer incidence. For prostate cancer (PCa) a prospective cohort study indicates that lower thyrotropin (TSH) and higher thyroxin (T4) levels are associated with an increased risk of PCa. However, triiodothyronine (T3) can attenuate PCa progression. Here we show that T3 treatment of human PCa cells reduces cell proliferation, by induction of cellular senescence. Interestingly, we could neither detect an increased expression of p16 nor p21 cell cycle inhibitors, which are mediators of the two major pathways for senescence induction. This suggests that the T3-induced cellular senescence of PCa cells is driven by an alternative pathway. We show that T3-mediated cellular senescence is associated with increase of DEC1 expression encoded by the BHLHE40 gene and p15 encoded by CDKN2B. Each DEC1/BHLHE40 and p15/CDKN2B knockdown reduced significantly the level of T3-mediated cellular senescence. The data suggest that DEC1 and p15 are crucial for the T3-induced cellular senescence. In line with a protective role of cellular senescence in cancer, public databases provide evidence linking low DEC1 expression to poor survival of PCa patients. Further we show that the BHLHE40 promoter is responsive to T3 suggesting BHLHE40 being a target gene for the thyroid hormone receptor (TR). Taken together, the data suggest that T3 mediates cellular senescence in PCa cells through induction of DEC1- and p15 -dependent pathway.
虽然有几项研究将甲状腺功能减退症与人类和老鼠的延长寿命联系起来，但甲状腺激素在癌症中的作用更具争议性，因为已知其具有促进肿瘤和抑制肿瘤的作用。一般来说，异常的甲状腺激素水平与癌症发病率的增加有关。对于前列腺癌（PCa），一项前瞻性队列研究表明，促甲状腺激素（TSH）水平较低和甲状腺素（T4）水平较高与 PCa 风险增加相关。然而，三碘甲状腺原氨酸（T3）可以抑制 PCa 的进展。在这里，我们表明 T3 处理人前列腺癌细胞通过诱导细胞衰老来减少细胞增殖。有趣的是，我们既没有检测到细胞周期抑制剂 p16 或 p21 的表达增加，它们是诱导衰老的两个主要途径的介质。这表明 T3 诱导的前列腺癌细胞衰老由替代途径驱动。我们表明，T3 介导的细胞衰老与 BHLHE40 基因编码的 DEC1 和 CDKN2B 基因编码的 p15 的表达增加有关。DEC1/BHLHE40 和 p15/CDKN2B 的每个敲低都显著降低了 T3 介导的细胞衰老水平。数据表明，DEC1 和 p15 对于 T3 诱导的细胞衰老至关重要。与细胞衰老在癌症中的保护作用一致，公共数据库提供的证据表明 DEC1 表达水平低与前列腺癌患者的生存率差有关。进一步表明 BHLHE40 启动子对 T3 有反应，提示 BHLHE40 是甲状腺激素受体（TR）的靶基因。总之，数据表明，T3 通过诱导 DEC1 和 p15 依赖性途径介导前列腺癌细胞的衰老。
