Abstract 3578: Novel insights into the cellular function and gene regulation of a master mutator, APOBEC3B

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Unequivocally, cumulative mutations are required for the development of cancer and many sources of mutagenic activity contribute to tumorigenesis. Recent evidence has implicated that a member of cytidine deaminase family, APOBEC3B (Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3B or A3B) is enriched in the genomes of many human cancers such as cervical, bladder, lung, head and neck and breast cancers (Burns et al., Nature, 2013). APOBEC3B deaminate cytosines in the host genome to generate C-T mutations. Here we report for the first time that APOBEC3B is overexpressed with adrenocortical carcinoma (ACC), a very aggressive and lethal malignancy. We found that APOBEC3B is significantly overexpressed in primary and metastatic ACC as compared to normal adrenal and cortical adenomas by qPCR, immunofluorescence. We observed that γH2AX, a marker of DNA double-strand breaks co-localizes with the expression of APOBEC3B in patients with primary and metastatic ACC. Also ACC tumor samples with high APOBEC3B expression had high chromosomal gain/loss particularly in chromosome 4 and 8 compared to tumor samples with low APOBEC3B expression. To identify the cellular function of APOBEC3B, we performed transient knock-down studies in three ACC cell lines and found that it reduces cellular proliferation and induces cell cycle arrest. Furthermore, we observed that knockdown of APOBEC3B inhibits MAPK signaling by downregulating phospho ERK1/2 levels. Interestingly, we found that tumors with high APOBEC3B expression levels had twice as many TP53 inactivating mutations as compared to tumors with low levels of APOBEC3B. In order to understand the regulation of APOBEC3B expression, we analyzed the methylation status, copy number variation and potential targeting miRNAs of APOBEC3B from genome wide array platform but found no associations in human ACC samples. Therefore, we did a functional, knockdown screen of 90 cancer-associated transcription factors and found that GATA3 showed positive regulation of APOBEC3B. Our data provide novel insights into the function and regulation of APOBEC3B expression beyond its known mutagenic ability. Citation Format: Sudheer Kumar Gara, Yi Liu-Chittenden, Shweta Kotian, Dhaval Patel, Electron Kebebew. Novel insights into the cellular function and gene regulation of a master mutator, APOBEC3B. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3578.