Rps6ka6, also known as ribosomal protein S6 kinase A6 or RSK4, encodes the p90 ribosomal S6 kinase-4. It is a downstream factor of the ERK-MAPK pathway [3,7]. Rps6ka6 may play a role in normal neuronal development as it is commonly deleted in patients with complex X-linked mental retardation [5]. It is also involved in various cellular processes and is thought to be associated with tumor-related functions [1,3,4,6,7,8].

In a study on CFW laboratory mice, deletion of exon 7 (Rps6ka6-ΔE7) in H2Kb myogenic cells using CRISPR-Cas9 method created a severely truncated RSK4 protein. The results showed that while myoblast proliferation and migration were not affected, indices of differentiation such as myosin expression, size of myosin-expressing cells, and fusion index were significantly reduced. This suggests that the X chromosome locus affects muscle fiber numbers in the fast-twitch extensor digitorum longus through the Rps6ka6 gene [2].

In thyroid cancer, FOXP2 binds directly to the promoter region of Rps6ka6 and transcriptionally activates it. Overexpression of FOXP2 inhibited cell proliferation and promoted apoptosis, and knockdown of Rps6ka6 reversed these effects, indicating that FOXP2 regulates thyroid cancer cell proliferation and apoptosis via Rps6ka6 [1].

In acute myeloid leukemia, Rps6ka6 expression was significantly decreased compared to non-AML patients, which may lead to increased activity of the ERK/MPAK pathway and exacerbate leukemogenesis [3].

In endometrial cancers, Rps6ka6 is frequently hypermethylated, leading to its epigenetic silencing, though its role as a suppressor in this cancer remains uncertain [4].

In lung squamous cell carcinoma, Rps6ka6 protein and mRNA expression was significantly higher in tumor tissues compared to normal tissues, and overexpression was correlated with tumor size, lymph node metastasis, and TNM stage, suggesting it may be an oncogene in this cancer type [7].

In conclusion, Rps6ka6 is involved in multiple biological processes. Its functions are revealed through gene-editing models in mice and cell-based functional studies. It plays important roles in muscle development and various cancers, such as thyroid, acute myeloid leukemia, endometrial, and lung squamous cell carcinoma. These findings from model-based research contribute to understanding the biological functions of Rps6ka6 and its potential as a therapeutic target in related diseases.

References:

1. Yang, Feibiao, Xiao, Zhangsheng, Zhang, Songze. 2022. FOXP2 regulates thyroid cancer cell proliferation and apoptosis via transcriptional activation of RPS6KA6. In Experimental and therapeutic medicine, 23, 434. doi:10.3892/etm.2022.11361. https://pubmed.ncbi.nlm.nih.gov/35607372/

2. Lekkos, Konstantinos, Bhuiyan, Afra A, Albloshi, Abdullah M K, Coate, Thomas M, Lionikas, Arimantas. . Validation of positional candidates Rps6ka6 and Pou3f4 for a locus associated with skeletal muscle mass variability. In G3 (Bethesda, Md.), 14, . doi:10.1093/g3journal/jkae046. https://pubmed.ncbi.nlm.nih.gov/38577978/

3. Rafiee, Mohammad, Keramati, Mohammad Reza, Ayatollahi, Hosein, Asgharzadeh, Ali, Alinejad, Mohsen. 2016. Down-Regulation of Ribosomal S6 kinase RPS6KA6 in Acute Myeloid Leukemia Patients. In Cell journal, 18, 159-64. doi:. https://pubmed.ncbi.nlm.nih.gov/27540520/

4. Dewdney, Summer B, Rimel, B J, Thaker, Premal H, Gao, Feng, Goodfellow, Paul J. 2011. Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers. In Clinical cancer research : an official journal of the American Association for Cancer Research, 17, 2120-9. doi:10.1158/1078-0432.CCR-10-2668. https://pubmed.ncbi.nlm.nih.gov/21372219/

5. Yntema, H G, van den Helm, B, Kissing, J, Cremers, F P, van Bokhoven, H. . A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. In Genomics, 62, 332-43. doi:. https://pubmed.ncbi.nlm.nih.gov/10644430/

6. Sun, Y, Cao, S, Yang, M, Song, X, Liao, D J. 2012. Basic anatomy and tumor biology of the RPS6KA6 gene that encodes the p90 ribosomal S6 kinase-4. In Oncogene, 32, 1794-810. doi:10.1038/onc.2012.200. https://pubmed.ncbi.nlm.nih.gov/22614021/

7. Fang, Ye-Ying, Ma, Fu-Chao, Gan, Xu-Li, Wei, Dan-Ming, Hu, Xiao-Hua. 2018. Clinicopathological significance of ribosomal protein S6 kinase A6 in lung squamous cell carcinoma: an immunohistochemical and RNA-seq study. In International journal of clinical and experimental pathology, 11, 1318-1327. doi:. https://pubmed.ncbi.nlm.nih.gov/31938227/

8. LLeonart, M E, Vidal, F, Gallardo, D, Carnero, A, Ramón y Cajal, S. . New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas. In Oncology reports, 16, 603-8. doi:. https://pubmed.ncbi.nlm.nih.gov/16865262/