Abstract
Iron homeostasis is critical to mammals, and dysregulation in iron homeostasis usually leads to severe disorders including various cancers. Massive hepcidin secretion is an indicator of thyroid cancer, but the molecular mechanisms responsible for this dysregulation are unknown. Hepcidin secretion from thyroid cancer cells also leads to decreased expression of the iron exporter, ferroportin (FPN), and increased intracellular iron retention, which promote cancer proliferation. In this study, we examined the role of hepcidin in thyroid cancer (TC) and the molecular bases of its signaling. Synthesis of hepcidin is regulated by the BMP4/7 agonist SOSTDC1, which was downregulated in TC; SOSTDC1 downregulation was correlated with G9a-mediated hypermethylation in its promoter. The binding of G9a to the SOSTDC1 promoter requires E4BP4, which interacts with G9a to form a multi-molecular complex that contributes to SOSTDC1 silencing. Silencing of E4BP4 or G9a has similar effects to SOSTDC1 overexpression, which suppresses secretion of hepcidin and inhibits TC cell proliferation. Furthermore, our in vivo xenograft data indicated that depletion of E4BP4 also inhibits cancer growth, reduces hepcidin secretion, and reduces G9a nuclear transportation. Iron homeostasis and tumor growth in TC may be regulated by an E4BP4-dependent epigenetic mechanism. These findings suggest a new mechanism of cellular iron dysfunction through the E4BP4/G9a/SOSTDC1/hepcidin pathway, which is an essential link in TC.
Highlights
Thyroid cancer (TC) is one of the frequent malignancies of the endocrine system, with a high incidence rate[1]
We found that hepcidin secretion level was significantly higher in TC patients than in healthy subjects (Fig. 1a)
We found that antibody-mediated blockade of hepcidin increased FPN in K1 and 8505C cells (Fig. 1e), but reduced intracellular iron content in K1 and 8505C cells (Fig. 1f)
Summary
Thyroid cancer (TC) is one of the frequent malignancies of the endocrine system, with a high incidence rate[1]. It can be divided into three subtypes, including differentiated papillary carcinoma, follicular carcinoma, and undifferentiated anaplastic carcinoma. It has been reported that genetic and epigenetic modifications are involved in TC1,2. There is a pressing need to determine the genetic factors contributing to TC. Recent studies have confirmed the indispensable role of iron in growth of cancer cell[5]. It has been shown that uptake, storage, and discharge of iron are altered in cancer cells, which facilitate their survival[5,6]
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