Class E basic helix-loop-helix protein 40 (bHLHe40) (Class B basic helix-loop-helix protein 2) (bHLHb2) (Differentially expressed in chondrocytes protein 1) (DEC1) (Enhancer-of-split and hairy-related protein 2) (SHARP-2) (Stimulated by retinoic acid gene 13 protein) [BHLHB2] [DEC1] [SHARP2] [STRA13]
развернуть
Thyroid hormone induces cellular senescence in prostate cancer cells through induction of DEC1.
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.
MeSH Terms
- Basic Helix-Loop-Helix Transcription Factors
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p15
- Homeodomain Proteins
- Humans
- Male
- Prostatic Neoplasms
- Thyroid Hormones
Keywords
- BHLHE40
- Cellular senescence
- DEC1
- Prostate cancer
- Thyroid hormone