Prr14, or Proline Rich 14, is a protein that plays crucial roles in organizing chromatin within the cell nucleus. It dynamically associates with the nuclear lamina and heterochromatin, specifically H3K9me3-modified heterochromatin, helping to spatially organize the eukaryotic genome [1,4,7]. Prr14 also activates the PI3K/Akt/mTOR signal pathway, which is involved in various cellular processes such as cell growth, survival, and metabolism [2,5,6,8].

Specific knockout (KO) of skeletal muscle Prr14 in mice led to muscle atrophy. Biochemical and high-throughput sequencing analysis showed that Prr14 deficiency altered chromatin structure, regulated MEF2C's activity, and disrupted myofiber identity maintenance, highlighting its role in mechanotransduction and epigenetic regulation in skeletal muscle [3]. In cancer studies, RNA interfering (RNAi)-mediated inhibition of Prr14 in human cutaneous squamous cell carcinoma (cSCC) cells suppressed cell proliferation, migration, and invasion, and promoted apoptosis, suggesting its potential as an oncogene in cSCC through the PI3K/Akt/mTOR signal pathway [2]. Similar effects were seen in colon cancer, where downregulation of Prr14 inhibited cell growth, migration, invasion, and the epithelial-mesenchymal transition (EMT) process [5].

In conclusion, Prr14 is essential for organizing heterochromatin at the nuclear lamina and is involved in key cellular signaling pathways. Mouse models with Prr14 knockout have been instrumental in revealing its role in skeletal muscle atrophy and in understanding its oncogenic potential in various cancers, thus providing insights into potential therapeutic targets for muscle-related pathologies and cancer treatment.

References:

1. Kiseleva, Anna A, Cheng, Yu-Chia, Smith, Cheryl L, Katz, Richard A, Poleshko, Andrey. . PRR14 organizes H3K9me3-modified heterochromatin at the nuclear lamina. In Nucleus (Austin, Tex.), 14, 2165602. doi:10.1080/19491034.2023.2165602. https://pubmed.ncbi.nlm.nih.gov/36633363/

2. Zhang, Lili, Yang, Jie, Ji, Zhoujing, Zhang, Jie, Yang, Shengju. 2023. PRR14 acts a novel oncogene activating the PI3K signal pathway in human cutaneous squamous cell carcinoma. In Journal of Cancer, 14, 1531-1540. doi:10.7150/jca.83695. https://pubmed.ncbi.nlm.nih.gov/37325059/

3. Yang, Mei, Wang, Jiajie, Liu, Zhongyue, Li, Zhihong. 2024. PRR14 mediates mechanotransduction and regulates myofiber identity via MEF2C in skeletal muscle. In Metabolism: clinical and experimental, 164, 156109. doi:10.1016/j.metabol.2024.156109. https://pubmed.ncbi.nlm.nih.gov/39706290/

4. Dunlevy, Kelly L, Medvedeva, Valentina, Wilson, Jade E, Poleshko, Andrey, Katz, Richard A. 2020. The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting. In Journal of cell science, 133, . doi:10.1242/jcs.240416. https://pubmed.ncbi.nlm.nih.gov/32317397/

5. Li, Fangfang, Zhang, Chundong, Fu, Lijuan. 2019. PRR14 overexpression promotes cell growth, epithelial to mesenchymal transition and metastasis of colon cancer via the AKT pathway. In PloS one, 14, e0218839. doi:10.1371/journal.pone.0218839. https://pubmed.ncbi.nlm.nih.gov/31596887/

6. Ren, Xiaolei, Long, Meijun, Li, Zhihong, Qi, Lin, Yang, Mei. 2020. Oncogene PRR14 promotes breast cancer through activation of PI3K signal pathway and inhibition of CHEK2 pathway. In Cell death & disease, 11, 464. doi:10.1038/s41419-020-2640-8. https://pubmed.ncbi.nlm.nih.gov/32541902/

7. Kiseleva, Anna A, Poleshko, Andrey. 2023. The secret life of chromatin tethers. In FEBS letters, 597, 2782-2790. doi:10.1002/1873-3468.14685. https://pubmed.ncbi.nlm.nih.gov/37339933/

8. Yang, M, Lewinska, M, Fan, X, Zhu, J, Yuan, Z-M. 2016. PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis. In Oncogene, 35, 5527-5538. doi:10.1038/onc.2016.93. https://pubmed.ncbi.nlm.nih.gov/27041574/