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The Atoh1 gene was first discovered in the Drosophila gene in 1998, and the variant of this gene was later found in almost all animal species genomes such as mice and humans. The Atoh1 gene is a functional gene that is transcribed into a 1065 bp long mRNA encoding a protein consisting of 354 amino acids, the transcription factor Atoh1, which is a member of the anterior neuron basic helix-loop-helix transcription factor family.
Atoh1 plays a role in the specificity of nerve cells in the central nervous system and peripheral nervous system and plays an important role in the development of secretory cells in the digestive tract. The study found that Atoh1 is a new anti-cancer gene. Closing this tumor suppressor gene can lead to cancer, and reopening this gene can help inhibit cancer. The Atoh1 gene controls the final step in cell differentiation, which ensures that the cell is positively defined without becoming a malignant cancer cell.
Figure 1. Summary of Atoh1 regulation. (Cheng, et al. 2017)
ATOH1 is a basic helix-loop-helix (BHLH) transcription factor that plays a key role in the development and regeneration of cochlear hair cells. ATOH1 is transcribed through a variety of signaling pathways, including Notch and Wnt signals. At the post-translational level, it is regulated by the ubiquitin-proteasome pathway. In vitro and in vivo studies have shown that manipulation of these signaling pathways not only controls development but also leads to regeneration of damaged cochlear hair cells. Recent advances in understanding the signaling networks involved in hair cell development and regeneration have led to the development of new strategies to replace lost hair cells.
Atoh1 and Brain Tumor
Sagal et al. studied the function of the neuronal transcription factor Atoh1 in neuronal differentiation of PSCs. It is shown that Atoh1 is induced during the neuronal transformation of human pluripotent stem cells (PSCs), and ectopic Atoh1 expression is sufficient to drive PSCs efficiently into neurons. The Atoh1 transcription factor plays a crucial role in the development of the cerebellum, and it is also implicated in certain other cancers in the brain, including medulloblastoma, the most common pediatric tumor in the nervous system. Studies have used a retroviral vector approach to eliminate the Atoh1 gene after birth. It was found that Atoh1 regulates the expression of the Gli2 gene and thus affects the so-called "Sonic Hedgehog" signaling pathway. This signaling pathway normally maintains the precursor cells of the cerebellum in an undifferentiated state. Accordingly, it is a delicate balance between cell proliferation and differentiation, this balance can lead to errors once tumor growth.
Atoh1 and Colon Cancer
The homolog Atoh1 gene in the Atonal gene group is associated with colon cancer. The main function of the Atoh1 gene is to regulate the final step of colonic epithelial cell differentiation. If this gene is lost or inactivated, it will cause colon cancer. Fukushima stabilizes Atoh1 protein by inactivating GSK-3β by Akt treatment with TNF-α, thereby producing carcinoma of colon and rectum (CRC) cell line. Atoh1 protein is also enriched in cancer stem cells, in which Lgr5 expression is up-regulated, cells are in the G0 / G1 cell cycle stage, resulting in chemical resistance to 5-fluorouracil and oxaliplatin and promoting cell migration. Immunofluorescence of human mucus colitis-associated colorectal cancer (CAC) specimens showed accumulation of NF-κBp65 in the nucleus and expression of Atoh1 in mucinous carcinoma. Kano et al. found that Atoh1 enhanced Wnt signaling, leading to the induction of Lgr5 as a representative stem cell marker with enrichment of cancer stem cells. In addition, a fluorescent ubiquitin-based cell cycle indicator system with delayed real-time imaging demonstrated cell cycle arrest in the G0 / G1 phase by Atoh1 protein stabilization. In conclusion, Atoh1 regulates the malignant potential rather than the differentiated phenotype of mucinous colon cancer (MC), suggesting that MC and signet ring cell carcinoma (SRCC) are more malignant than non-mucinous adenocarcinoma.
Atoh1 and Merkel Cell Carcinoma
Merkel cell carcinoma (MCC), also known as neuroendocrine cell carcinoma, is a low-grade malignant tumor that originates in the skin tactile body Merkel cells. Atoh1 may be an early indicator of carcinogenic mutations in tissues that direct cell differentiation. To validate this possibility in vivo, the researchers collected samples from 4 patients with MCC to investigate whether the Atoh1 gene has a down-regulation trend. Genomic DNA samples were detected by quantitative polymerase chain reaction. Expression analysis of MCC cell lines showed a negative correlation between Atoh1 levels and Merkel cell growth. The data support that Atho1 is an evolutionarily conserved tumor suppressor gene, and loss of Atoh1 promotes tumor formation and progression, and mutations occur at a higher frequency at the Atoh1 locus. Given the high deletion and methylation ratio of Atoh1, loss of Atoh1 function may be an early sign of the tumor.
Gambichler et al. successfully performed genomic DNA isolation and PCR amplification in 33 formalin-fixed paraffin-embedded tissues and three MCC cell lines, followed by Sanger sequencing of the entire ATOH1 gene to detect genomic aberrations. The research team determined the ATOH1 mRNA level by RT-PCR and immunohistochemical analysis of ATOH1 to quantify protein expression in tumor samples and cell lines, and found that genetic changes in MCC did not lose ATOH1 expression. However, protein expression of ATOH1 increased in late MCC, indicating that ATOH1 is involved in MCC progression.
Based on the above, Atoh1 is a useful diagnostic tool for the early detection and diagnosis of MCC. Similarly, treatment with MCC patients showed that Atoh1 epigenetic silencing is a powerful therapeutic approach with DNA methyltransferase inhibitors, as this restores Atoh1 expression and induces cancer cell death.