According to the latest data released by the International Agency for Research on Cancer (IARC), there were 19.29 million new cancer cases worldwide in 2020, with 9.96 million new cancer-related deaths. Cancer remains a leading cause of death globally, often referred to as the “king of diseases.” As life expectancy continues to rise, the incidence of cancer is expected to further increase. The development of cancer is a complex, multistep process involving multiple cellular regulatory pathways, with an imbalance between oncogenes and tumor suppressor genes being a critical factor.
Since its discovery in 1979, the p53 gene (TP53) has been a focal point in the field of oncology. A search for “p53” in the PubMed database yields over a hundred thousand articles. In a 2017 analysis published in the journal Nature, the p53 gene ranked first on the list of the most studied genes in the past few decades.
In various types of tumors, p53 is a potent tumor suppressor gene with broad and powerful functions, often referred to as the “genome guardian.” p53 responds to various cellular stressors, such as DNA damage, by becoming activated. Its activation promotes DNA repair or induces controlled cell death, thereby preventing the onset and progression of cancer. Consequently, p53 gene mutations are highly common in many cancers, with approximately half of cancer patients carrying p53 gene mutations. Mutations in the p53 gene are pivotal drivers in the occurrence, development, treatment resistance, and poor prognosis of cancer.
Recently, researchers at the Wistar Institute in the United States published a study in the journal Cancer Discovery titled “An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression.”
This study identified a rare TP53 mutation variant in African American individuals, where amino acid 107 in the DNA-binding domain was mutated from tyrosine to histidine (Y107H). The TP53-Y107H mutation affected the epigenetic modifier PADI4, revealing PADI4 as a regulator of p53-mediated tumor suppression.
TP53 encodes the critical tumor suppressor protein p53, which regulates many essential cellular processes, including transcription, metabolism, cell cycle arrest, apoptosis, senescence, and immune signaling, among others. In a metaphorical sense, p53 acts as a faithful guardian within cells, playing a crucial role in clearing defective or inactive cells from the tissue, ensuring the orderly functioning of cells.
Because TP53 plays such a vital role, mutations and loss of function can have devastating consequences. Statistics show that TP53 is the most commonly mutated gene in cancer, with mutations present in approximately half of all human tumors. However, the key target genes responsible for p53 protein-mediated tumor suppression have not been definitively identified.
In this latest study, the research team aimed to determine how p53 inhibits tumors by exploring how specific TP53 mutations fail to suppress cancer. In simpler terms, they underwent a “paradigm shift” in their thinking, focusing not on “what does p53 do,” but rather on “what can’t it do when it fails to suppress cancer.”
Given that cancer burden among African Americans is the highest of all racial groups worldwide, the research team screened TP53 mutations in cancer datasets and identified a unique variant specific to African ancestry, named Y107H, present in approximately 0.001% of individuals of African descent.
Similar to other missense variants such as P47S and G334R, nuclear magnetic resonance and crystal structure studies revealed that Y107H closely resembles the wild-type p53 in structure, with Y107H variant retaining most of the wild-type p53 functions, except for a deficiency in transcriptional activation of p53 target genes.
Subsequently, the research team used CRISPR gene editing technology to create TP53-Y107H tumor cell lines and mouse models. By comparing genes that could be activated by wild-type p53 but not by the Y107H mutant, researchers identified an epigenetic modifier called PADI4, which is prone to mutations and inactivation in some human tumors.
Further investigation showed that PADI4 contributes to the immune system’s ability to recognize tumors by modifying amino acid residues of tumor proteins. PADI4 can convert arginine to citrulline, a non-natural amino acid. The immune system perceives citrulline as an aberrant invader and attacks the target cells, thereby inhibiting and eliminating tumor cells.
Interestingly, PADI4 also exhibited impaired transcriptional activation in several other p53 missense variants, such as P47S and G334R. This suggests that PADI4 is highly sensitive to functional mutations in p53 and is likely a key target gene in p53 protein-mediated tumor suppression.
Furthermore, the research team used bioinformatics approaches to identify genes co-regulated by p53 and PADI4, creating a gene set. They analyzed data from 60,000 tumors in The Cancer Genome Atlas (TCGA) database and identified five genes jointly regulated by wild-type p53 and PADI4, which could not be activated in the Y107H mutant. This five-gene signature can predict cancer survival, tumor immune infiltration, and the efficacy of immunotherapy.
In summary, this study discovered the African-specific variant of TP53, Y107H, and demonstrated the crucial role of PADI4 as a regulator of p53 protein-mediated tumor suppression. These findings shed light on the differences in African American cancer, personalized medical approaches, and the key target genes in p53-mediated tumor suppression. They hold promise for predicting the efficacy of immunotherapy and improving the prognosis of cancer patients, paving the way for the development of new cancer monitoring methods.
Reference
1. Indeglia, Alexandra, et al. “An African-Specific Variant of TP5 3 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.” Cancer Discovery (2023): OF1-OF24.