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 p16INK4A nor p21CIP1 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 p15INK4B encoded by CDKN2B. Each DEC1/BHLHE40 and p15INK4B/CDKN2B knockdown reduced significantly the level of T3-mediated cellular senescence. The data suggest that DEC1 and p15INK4B 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 p15INK4B -dependent pathway.

中文翻译：

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甲状腺激素通过诱导DEC1诱导前列腺癌细胞的细胞衰老。

尽管有几项研究将甲状腺功能减退症的状态与人类和小鼠的寿命延长联系起来，但甲状腺激素在癌症中的作用却更具争议性，因为已知其具有促进肿瘤和抑制肿瘤的作用。通常，甲状腺激素水平异常与癌症发生率增加有关。对于前列腺癌（PCa），一项前瞻性队列研究表明，较低的促甲状腺激素（TSH）和较高的甲状腺素（T4）水平与PCa风险增加相关。但是，三碘甲状腺素（T3）可以减弱PCa的进程。在这里，我们显示T3对人PCa细胞的治疗通过诱导细胞衰老来降低细胞增殖。有趣的是，我们无法检测到p16INK4A和p21CIP1细胞周期抑制剂的表达增加，它们是衰老诱导的两个主要途径的介体。这表明T3诱导的PCa细胞衰老是由另一种途径驱动的。我们表明，T3介导的细胞衰老与BHLHE40基因编码的DEC1表达和CDKN2B编码的p15INK4B的表达增加有关。每种DEC1 / BHLHE40和p15INK4B / CDKN2B组合均能显着降低T3介导的细胞衰老水平。数据表明DEC1和p15INK4B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相一致，公共数据库提供了将DEC1低表达与PCa患者生存不良联系起来的证据。此外，我们显示BHLHE40启动子对T3有反应，表明BHLHE40是甲状腺激素受体（TR）的靶基因。在一起