Abstract
CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (−257 to −143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.
Highlights
As one of the most common cancers originated from the endocrine system, the incidence of thyroid cancer has been increasing rapidly worldwide [1]
To investigate the role of CRSP8 in thyroid cancer progression, we first analyzed its expression in human normal thyroid cells, differentiated thyroid cancer (DTC) cells, and anaplastic thyroid cancer (ATC) cells
Compared to normal thyroid cells, CRSP8 was highly expressed in human thyroid cancer cells, especially in ATC, and mainly located in the nucleus (Fig. 1A, B)
Summary
As one of the most common cancers originated from the endocrine system, the incidence of thyroid cancer has been increasing rapidly worldwide [1]. Thyroid cancers are derived from two types of endocrine thyroid cells, follicular thyroid cells, and parafollicular C cells. Follicular thyroid cell-derived tumors, including papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC), account for the majority of thyroid malignancies, while parafollicular C cell-derived medullary thyroid cancer accounts for only a small proportion. PDTC and ATC are much less common, aggressive, and lethal with rapid progression, forming the main cause of thyroid cancerrelated mortality [3,4,5]. The mechanisms underlying the regulation of poor differentiation or anaplastic phenotype in PDTC and ATC deserve in-depth investigation to provide more effective therapeutic strategies
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