In the body, there are thousands of cells mutated due to DNA errors lurking every day, and they all have the possibility of eventually causing cancer. Existing theories believe that cancer is caused by two types of gene mutations: mutations of proto-oncogenes and inactivation of tumor suppressor genes, however, not all genetic mutations cause cancer. Take the mole on the body as an example, gene mutations can cause the mole to become cancerous and form melanoma. It is worth noting that most moles will never become cancerous. Scientists have been working to unravel the reasons for this difference, and this problem has finally been overcome recently.
Recently, a new study has discovered the key component that affects the carcinogenesis of melanocytes-the chromatin-modifying enzyme ATAD2 protein in the cellular environment. This gene can bind to different regions of the chromosome to activate genes related to cell embryonic development, thereby increasing mutations. The carcinogenic ability of proto-oncogenes promotes the formation of cancer and thus proposes the third key factor affecting cell carcinogenesis, that is, the carcinogenic ability initiated by the cellular environment.
Melanoma is associated with BRAF gene mutations. In this study, the researchers first drove BRAF gene expression in a zebrafish model and allowed it to be in the neural crest phase (early development) of melanocytes and the melanoblast phase (middle development). ), and three stages of maturation to activate cancer cells. The test results show that melanocytes have a strong transcriptional response to BRAF gene in the early and middle developmental stages, and both activate cancer cells. In contrast, the transcriptional response of mature melanocytes to BRAF gene is almost deletion, almost no gene mutation.
To extend the research to human cells, the researchers developed a human pluripotent stem cell (hPSC)-derived tumor model, divided it into three stages, and transplanted it into mice. Studies have shown that similar to the findings in the zebrafish model, human mature melanocytes are relatively resistant to malignant transformation, while early and mid-stage melanocytes are prone to develop tumors.
What are the essential differences between the cell types in these three stages? After they were analyzed by the GSAA pathway, the results showed that several chromatin-modifying enzymes including ATAD2, BPTF, BAZ1A, and EZH2 were significantly up-regulated in early and mid-stage melanocytes. As a result, the researchers hypothesized that these chromatin-modifying enzymes may be the “culprits” that cause early and mid-stage melanocytes to become cancerous
Through further research, the researchers found that one of the chromatin-modifying enzymes, ATAD2, is usually amplified or overexpressed in melanoma patients. In order to verify the key role of ATAD2 in the formation of melanoma, the researchers first removed ATAD2 in the melanoma zebrafish model. The results showed that after removal, the melanocytes lost the ability to become cancerous, and then ATAD2 was added to the melanocytes again, and the cells regained the ability to cause cancer. This means that ATAD2 is a key factor in the smooth formation of melanoma.
Researchers continue to use the large amount of data provided by MSK and Cancer Genome Atlas to verify, and the results prove that the survival rate of cancer patients activated by ATAD2 is significantly reduced, which shows that it does play an important role in the cancer genome. In general, the new discovery of ATAD2 protein in melanoma will not only provide new drug targets for cancer treatment. More importantly, the third-factor theory of carcinogenicity proposed for the formation of cancer this time is in sharp contrast with the traditional theory and provides new theoretical insights for cancer treatment.