Sex-Specific Expression of Histone Lysine Demethylases (KDMs) in Thyroid Cancer

Simple Summary Thyroid cancer is the most common endocrine malignancy and is more frequently detected in women than in men. An understanding of the molecular features governing thyroid carcinogenesis in women and men may open avenues toward the development of sex-specific treatments for female and male patients with thyroid cancer. To this end, we performed an analysis of sex-biased genes in normal thyroids as well as benign and malignant thyroid tumors. We demonstrated that normal thyroid tissue has a sex-specific molecular signature, and the development of thyroid cancer is associated with the differential expression of sex-biased genes. In confirmatory studies, we demonstrated that the expression of histone lysine demethylases (KDMs) is strongly associated with sex. Together, our data demonstrate that the development of thyroid cancer may be associated with different sex-specific molecular changes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may provide a clue for understanding the mechanisms underlying sex differences in thyroid tumorigenesis. Abstract Background: The incidence of thyroid cancer in women is 3–4-fold higher than in men. To characterize sex-specific molecular alterations in thyroid cancer, we examined the expression of sex-biased genes in normal thyroids and thyroid tumors. Methods: Ingenuity pathways analysis was used to define sex-biased gene networks using data from the Cancer Genome Atlas (TCGA). Confirmatory studies were performed through the analysis of histone lysine demethylases (KDMs) expression by real-time PCR and immunostaining. Results: In normal thyroids, 44 sex-biased genes were comparatively upregulated in male and 28 in female patients. The expressions of 37/72 (51%) sex-biased genes were affected in cancer tissues compared with normal thyroids. Gene network analyses revealed sex-specific patterns in the expressions of KDM5C, KDM5D, and KDM6A. In confirmatory studies, KDM5D mRNA and protein were detected only in males, whereas KDM5C and KDM6A were detected in samples from male and female patients. Nuclear staining with anti-KDMs was found in normal thyroids, but a loss of nuclear expression with a concomitant gain of cytoplasmic staining was observed in cancer tissues. Conclusions: Normal thyroids have a sex-specific molecular signature, and the development of thyroid cancer is associated with a differential expression of sex-biased genes. The sex-specific expression of KDMs, coupled with cancer-related alterations in their intracellular localization, may contribute to mechanisms underlying sex differences in thyroid tumorigenesis.

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