Zc3h3, a zinc-finger protein, has multiple essential functions. It is involved in m6A RNA modification as an m6A methyltransferase, which is a prevalent and conserved internal cotranscriptional modification in eukaryotic RNAs, playing crucial roles in both physiological and pathological conditions, especially in cancer [1]. Additionally, Zc3h3 is critical for the Poly(A) Tail eXosome Targeting (PAXT)-mediated nuclear RNA decay, interacting directly with MTR4-ZFC3H1, and its loss leads to the accumulation of PAXT substrates [2]. It also interfaces between the polyadenylation machinery, newly poly(A) mRNAs, and factors for transcript export, as depletion of its Drosophila homologue dZC3H3 results in transcript hyperadenylation, and depletion of human Zc3H3 causes an mRNA export defect [3].

In cancer-related studies, increased transcriptional levels of Zc3H3 were observed in hepatocellular carcinoma (HCC), indicating its potential importance in the development of fibrosis and HCC, and suggesting it as a potential therapeutic target and diagnostic tool [4]. In adrenocortical carcinoma (ACC), Zc3H3 was overexpressed, and the expression of m6A-related genes including Zc3H3 could be used as an independent prognostic factor [6]. In adenocarcinoma at the gastroesophageal junction, Zc3H3 was selected to construct a prognostic model, and high-risk patients based on this model had significantly worse overall survival [5].

In conclusion, Zc3h3 is involved in m6A RNA modification, nuclear RNA decay, and mRNA export-related processes. Its dysregulation is associated with various cancers such as HCC, ACC, and adenocarcinoma at the gastroesophageal junction. Research on Zc3h3 using gene-knockout models (if applicable in these studies) could potentially further clarify its role in these disease conditions, providing more insights for targeted therapies.

References:

1. Jiang, Xiulin, Liu, Baiyang, Nie, Zhi, Yang, Cuiping, Chen, Yongbin. 2021. The role of m6A modification in the biological functions and diseases. In Signal transduction and targeted therapy, 6, 74. doi:10.1038/s41392-020-00450-x. https://pubmed.ncbi.nlm.nih.gov/33611339/

2. Silla, Toomas, Schmid, Manfred, Dou, Yuhui, Landthaler, Markus, Jensen, Torben Heick. . The human ZC3H3 and RBM26/27 proteins are critical for PAXT-mediated nuclear RNA decay. In Nucleic acids research, 48, 2518-2530. doi:10.1093/nar/gkz1238. https://pubmed.ncbi.nlm.nih.gov/31950173/

3. Hurt, Jessica A, Obar, Robert A, Zhai, Bo, Gygi, Steven P, Silver, Pamela A. 2009. A conserved CCCH-type zinc finger protein regulates mRNA nuclear adenylation and export. In The Journal of cell biology, 185, 265-77. doi:10.1083/jcb.200811072. https://pubmed.ncbi.nlm.nih.gov/19364924/

4. Kurokawa, Suguru, Kobori, Takuro, Yoneda, Masato, Nakajima, Atsushi, Hotta, Kikuko. 2024. Identification of differentially methylated regions associated with both liver fibrosis and hepatocellular carcinoma. In BMC gastroenterology, 24, 57. doi:10.1186/s12876-024-03149-3. https://pubmed.ncbi.nlm.nih.gov/38302914/

5. Lao, Yueqiong, Wang, Yuqian, Yang, Jie, Xi, Yiyi, Zhong, Ce. 2022. Characterization of genomic alterations and neoantigens and analysis of immune infiltration identified therapeutic and prognostic biomarkers in adenocarcinoma at the gastroesophageal junction. In Frontiers in oncology, 12, 941868. doi:10.3389/fonc.2022.941868. https://pubmed.ncbi.nlm.nih.gov/36439494/

6. Fu, Yang, Sun, Shanshan, Bi, Jianbin, Kong, Chuize, Yin, Lei. . Expression patterns and prognostic value of m6A RNA methylation regulators in adrenocortical carcinoma. In Medicine, 100, e25031. doi:10.1097/MD.0000000000025031. https://pubmed.ncbi.nlm.nih.gov/33725886/