NIH Research Festival
The success of precision medicine of oncology requires implementing new algorithms and detailed understanding of genetic alterations in each cancer type. Recent genome-wide sequencing studies in various cancers identified many previously under-appreciated genetic alterations and genes. It remains challenging to prioritize and determine the functions of these genetic alterations. To increase the probability of finding functionally important cancer genes, we developed a new p53 Mutual Exclusivity Algorithm (PMEA) which tests the mutual exclusivity of p53 mutations and the mutations of a candidate gene. Since p53 is a well-established tumor suppressor, we reasoned that if the mutations of a gene are mutually exclusive to p53 mutations, this gene may functionally connect to the p53 signaling pathway and likely act a driver gene in cancer. As a proof-of-concept, we applied PMEA to two breast cancer datasets: TCGA and METABRIC and identified several genes, such as GATA3, PIK3CA, MAP3K1, CDH1 and CBFB, whose mutations are significantly mutually exclusive to p53 mutations. We chose to study the roles of breast tumor-derived CBFB mutants because its role in breast cancer is under-studied. CBFB is a part of transcription factor complex where it interacts with its partner RUNX1 to stabilize its interaction with DNA to regulate transcription. We observed that in breast cancer cells and human tumor samples instead of being a part of transcription factor complex CBFB mostly localizes in cytoplasm while its partner RUNX1 is exclusively present in nucleus. CRISPR-Cas9 based knockout of CBFB in non-tumorigenic MCF10A induced cell transformation and in vivo tumorigenesis. Interestingly, loss of CBFB resulted in concomitant loss of RUNX1 protein indicating CBFB is regulating RUNX1. We discovered a surprising cytoplasmic function of CBFB, in promoting the translation of RUNX1. Mechanistically, CBFB is recruited to the 3’ untranslated region of RUNX1 mRNA by HnRNPK (known mRNA processor). CBFB and HnRNPK co-operatively regulate translation of RUNX1. Genomic studies reveal that the CBFB/RUNX1 axis and p53 co-induce p73, therefore providing a rationale to the mutual exclusivity of CBFB and p53 mutations. Furthermore, the CBFB/RUNX1 axis represses the oncogenic NOTCH3 signaling pathway to suppress breast cancer. Our results establish an unanticipated cytoplasmic role of CBFB in RUNX1 translation, and this non-transcriptional mechanism may be therapeutically exploited.
Scientific Focus Area: Cancer Biology
This page was last updated on Friday, March 26, 2021