Zcchc13, zinc-finger CCHC-type containing 13, is located in an imprinted gene cluster in the X-inactivation centre [3]. The CCHC-type zinc finger motif it contains endows it with numerous biological activities like DNA and RNA binding, and mediating protein-protein interactions. It is involved in regulating cell cycle-related pathways and is of significance in embryonic development and reproduction-related processes [1,3,4].

In hepatocellular carcinoma (HCC), Zcchc13 functions as an oncogene. Its overexpression in HCC cells is due to DNA hypomethylation in the promoter region. It promotes cell cycle progression by facilitating the G1-S transition through the aberrant activation of the ATK/ERK/c-MYC/CDK pathway [1]. In non-obstructive azoospermia (NOA), ZCCHC13 protein expression is decreased. It positively regulates the AKT/MAPK/c-MYC pathway, and methylation aberrations of ZCCHC13 may cause defects in testis development [2]. It has also been associated with semen quality and fertility in breeding bulls [4], and as a biomarker in breast cancer prediction [5]. Additionally, it has been identified as a potentially causally defective gene in NOA [6].

In conclusion, Zcchc13 plays crucial roles in cell cycle regulation, embryonic development, and reproduction. Studies on Zcchc13 in various disease models, such as HCC and NOA, have revealed its significance in cancer development and male infertility, providing insights into potential therapeutic targets and diagnostic biomarkers.

References:

1. Li, Zhiming, Li, Zhi, Wang, Linjun, Zheng, Zaozao, Zhuang, Xuan. 2019. ZCCHC13-mediated induction of human liver cancer is associated with the modulation of DNA methylation and the AKT/ERK signaling pathway. In Journal of translational medicine, 17, 108. doi:10.1186/s12967-019-1852-0. https://pubmed.ncbi.nlm.nih.gov/30940166/

2. Li, Zhiming, Chen, Shuai, Yang, Yufeng, Zhuang, Xuan, Tzeng, Chi-Meng. 2018. Novel biomarker ZCCHC13 revealed by integrating DNA methylation and mRNA expression data in non-obstructive azoospermia. In Cell death discovery, 4, 36. doi:10.1038/s41420-018-0033-x. https://pubmed.ncbi.nlm.nih.gov/29531833/

3. Kobayashi, Shin, Totoki, Yasushi, Soma, Miki, Okabe, Masaru, Ishino, Fumitoshi. 2013. Identification of an imprinted gene cluster in the X-inactivation center. In PloS one, 8, e71222. doi:10.1371/journal.pone.0071222. https://pubmed.ncbi.nlm.nih.gov/23940725/

4. Swathi, Divakar, Ramya, Laxman, Archana, Santhanahalli Siddalingappa, Binsila, Bala Krishnan, Selvaraju, Sellappan. 2022. X chromosome-linked genes in the mature sperm influence semen quality and fertility of breeding bulls. In Gene, 839, 146727. doi:10.1016/j.gene.2022.146727. https://pubmed.ncbi.nlm.nih.gov/35835407/

5. Taghizadeh, Eskandar, Heydarheydari, Sahel, Saberi, Alihossein, JafarpoorNesheli, Shabnam, Rezaeijo, Seyed Masoud. 2022. Breast cancer prediction with transcriptome profiling using feature selection and machine learning methods. In BMC bioinformatics, 23, 410. doi:10.1186/s12859-022-04965-8. https://pubmed.ncbi.nlm.nih.gov/36183055/

6. Sharifi, Shahrashoub, Dursun, Murat, Şahin, Ayla, Palanduz, Şükrü, Kadıoğlu, Ateş. 2025. Genetic insights into non-obstructive azoospermia: Implications for diagnosis and TESE outcomes. In Journal of assisted reproduction and genetics, 42, 1223-1237. doi:10.1007/s10815-025-03409-5. https://pubmed.ncbi.nlm.nih.gov/39932629/