Oncotarget: GATA3 and APOBEC3B are prognostic markers in adrenocortical carcinoma

The cover for issue 36 of Oncotarget features Figure 7, "Knockdown of APOBEC3B is associated with a lower tumor growth in an adrenocortical carcinoma xenograft mouse model," by Gara, et al. which reported that the role of APOBEC3B in adrenocortical carcinoma and the mechanisms through which its expression is regulated in cancer are not fully understood.

Here, the authors report that APOBEC3B is overexpressed in ACC and it regulates cell proliferation by inducing S phase arrest. They show high APOBEC3B expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and TP53 mutation rate in ACC.

GATA3 was identified as a positive regulator of APOBEC3B expression and directly binds the APOBEC3B promoter region.

Both GATA3 and APOBEC3B expression levels were associated with patient survival.

This Oncotarget study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

This Oncotarget study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

Dr. Electron Kebebew from Stanford University said, "Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy."

The distinct pattern of DNA base alterations has been characterized in the cancer genome using high throughput deep sequencing technologies, that reflect the underlying mutational process.

Whole-genome and exome mutation analysis of The Cancer Genome Atlas data on multiple cancers has revealed that this pattern is consistent with the deaminase activity of the AID/APOBEC family of enzymes, therefore, implying its significance as an endogenous mutator and a crucial contributor to somatic mutations and genomic instability.

APOBEC3B is overexpressed in ovarian cancer cell lines and high-grade primary ovarian cancers.

Figure 7: Knockdown of APOBEC3B is associated with a lower tumor growth in an adrenocortical carcinoma xenograft mouse model. (A) APOBEC3B protein expression in H295R cells stably transfected with four different shRNAs targeting APOBEC3B. shRNA 2 and shRNA 4 were selected for in vivo experiments based on the efficiency. (B) Tumor growth curve in NOD scid gamma (NSG) mice that received a vector control, APOBEC3B shRNA2, and 4 stably transfected H295R cells flanks on either side. A total of eight mice per each group were used for this study. Three of the control mice died in the first week after injection for unrelated reasons. The error bars represent the standard error mean (SEM). ^*Indicates p < 0.05. (C) The tumor weight of each group at the time of sacrifice (8 weeks after xenograft). (D) The isolated tumors from each group at the time of sacrifice.

In addition, APOBEC3B expression is positively correlated with the total mutation load, as well as, elevated levels of transversion mutations.

Given there are no well-established exogenous factors associated with ACC, the Oncotarget authors postulated whether APOBEC3B could be an endogenous mechanism of genomic instability/mutations in ACC and investigated its function in vitro and in vivo.

The Kebebew Research Team concluded in their Oncotarget Research Paper, "APOBEC3B overexpressed in ACC, and is associated with DNA damage, S phase arrest, higher copy number alterations and TP53 mutations in ACC. For the first time, we demonstrated that GATA3 directly regulates the expression of APOBEC3B and that both are prognostic markers in ACC."

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DOI - https://doi.org/10.18632/oncotarget.27703

Full text - https://www.oncotarget.com/article/27703/text/

Correspondence to - Electron Kebebew - kebebew@stanford.edu

Keywords - adrenocortical carcinoma, APOBEC3B, GATA3, prognosis, DNA damage

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