Preventing BRCA1/ZBRK1 repressor complex binding to the GOT2 promoter results in accelerated aspartate biosynthesis and promotion of cell proliferation

Abstract

Breast cancer susceptibility gene 1 (BRCA1) has been implicated in modulating metabolism via transcriptional regulation. However, direct metabolic targets of BRCA 1 and the underlying regulatory mechanisms are still unknown. Here, we identified several metabolic genes, including the gene which encodes glutamate‐oxaloacetate transaminase 2 ( GOT 2), a key enzyme for aspartate biosynthesis, which are repressed by BRCA 1. We report that BRCA 1 forms a co‐repressor complex with ZBRK 1 that coordinately represses GOT 2 expression via a ZBRK 1 recognition element in the promoter of GOT2 . Impairment of this complex results in upregulation of GOT 2, which in turn increases aspartate and alpha ketoglutarate production, leading to rapid cell proliferation of breast cancer cells. Importantly, we found that GOT 2 can serve as an independent prognostic factor for overall survival and disease‐free survival of patients with breast cancer, especially triple‐negative breast cancer. Interestingly, we also demonstrated that GOT 2 overexpression sensitized breast cancer cells to methotrexate, suggesting a promising precision therapeutic strategy for breast cancer treatment. In summary, our findings reveal that BRCA 1 modulates aspartate biosynthesis through transcriptional repression of GOT 2, and provides a biological basis for treatment choices in breast cancer.

Identification of three m6A‐related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma

“…[25][26][27] CSAD maintains its high expression when stimulated in the precancerous liver, 28 and gene polymorphisms of GOT2 are closely related to occupational exposure to liver injury, 29 and in particular, GOT2 was found to be involved in many cancers, such as pancreatic tumors. 30 Hong et al reported that BRCA1 modulates aspartate biosynthesis through transcriptional repression of GOT2, 31 while Maren Feist et al reported that GOT2 is a biomarker of lymphoma. 32 Similarly, many studies have shown that SOCS2 plays an important role in inhibiting the progression of liver cancer.…”

Survival-Associated Metabolic Genes in Human Papillomavirus-Positive Head and Neck Cancers

“…This means that while GOT2 may be important for survival outcomes in both HPV+ and HPV-HNSCC, it is likely that it has a more substantial contribution to patient survival in HPV+ HNSCC. In breast cancer, sensitivity to a nucleotide synthesis inhibitor, methotrexate, has been linked to high GOT2 expression [40]. This is likely due to the function of GOT2 in providing aspartate for nucleotide biosynthesis [40].…”

“…In breast cancer, sensitivity to a nucleotide synthesis inhibitor, methotrexate, has been linked to high GOT2 expression [40]. This is likely due to the function of GOT2 in providing aspartate for nucleotide biosynthesis [40]. It is possible that HPV+ HNSCCs, or potentially any HNSCCs expressing high levels of GOT2, may be sensitive to methotrexate, but this remains to be explored.…”

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

“…Hong and colleagues showed that the breast cancer susceptibility gene 1 ( BRCA1 )-encoded protein BRCA1 formed a co-repressor complex with Zinc finger and BRCA1-interacting protein with KRAB domain-1 (ZBRK1) on the GOT2 promoter via the ZBRK1 recognition element, suppressing its transcription [ 42 ]. Overexpression of mCAT is frequently reported in breast cancer.…”

“…Furthermore, BRCA1 deficiency accelerated tumor growth along with GOT2 upregulation by its transcriptional activation (or derepression), which indicates that mCAT could act as a metabolic malignancy driver in the absence of BRCA1 or ZBRK1 in breast cancer. Interestingly, the authors also reported that mCAT-overexpressing breast cancer cells were more sensitive to methotrexate treatment, suggesting this enzyme as a possible marker towards personalized medicine, aiming to anticipate therapy resistance in these breast cancer patients [ 42 ]. However, BRCA1 loss-of-function may explain these results, possibly limiting the beneficial benchmarking of mCAT expression in patients with BRCA1 mutations.…”