Abstract 2600: BBOX1 is a novel tumor suppressor in kidney cancer

Abstract

Abstract Renal cell carcinoma (RCC) is a common type of cancer with a steady increase in new cases and deaths for the past several decades while its development is not fully understood. We previously identified the γ-butyrobetaine hydroxylase 1 (BBOX1), a member of the 2-oxoglutarate dependent dioxygenase family whereas functionally uncharacterized previously in human cancers, plays a vital oncogenic role in triple-negative breast cancer. However, the role of BBOX1 in other cancers such as kidney cancer remains unclear. We found that BBOX1 is a highly context-dependent enzyme, reflected by its expression only detected in a few organs such as kidney. Intriguingly, according to our immunohistochemistry staining results and the data from The Human Protein Atlas database, BBOX1 is only expressed in the proximal tubule cells where clear cell RCC (ccRCC, the most common form of kidney cancer) derives from, indicating a connection of BBOX1 with kidney malignant transformation. In this study, we investigated the BBOX1 mRNA and protein expression in paired normal and tumor ccRCC patient samples from the UTSW Kidney Cancer Specialized Program of Research Excellence (SPORE) program, as well as patient data from The Cancer Genome Atlas (TCGA) or Clinical Proteomic Tumor Analysis Consortium (CPTAC), which consistently showed that BBOX1 is remarkably downregulated in the ccRCC patient tumors compared to normal kidneys, and its low expression associates with worse prognosis in ccRCC patients. Furthermore, expression of BBOX1 was highly presented in the human primary renal proximal tubule epithelial cells (RPTEC) while robustly suppressed after malignant transformation of the RPTEC cells. These data suggest a pathological loss of BBOX1 during RCC progression. Restoration of BBOX1 in multiple human ccRCC cell lines suppressed xenograft tumor growth in mice but not in the 2D in vitro growth with normal tissue culture conditions, suggesting BBOX1 plays an important role in ccRCC tumor development. By comparing the gene expression profiles from transcriptomics analyses in the control or BBOX1 overexpression samples either from xenograft tumors or cells grown in normal 2D culture, we found that BBOX1 suppresses the mTORC1 signaling only in the in vivo condition. Interestingly, we could recapitulate this phenomenon by culturing the control or BBOX1 overexpression ccRCC cells in a physiologic medium but not the standard cell culture medium. These data suggested BBOX1 may regulate the mTORC1 signaling depending on the nutrient status of the tumor cells. Overall, we identified BBOX1 as a novel tumor suppressor in ccRCC. Citation Format: Chengheng Liao, Liwei Jia, Hua Zhong, Lianxin Hu, Payal Kapur, James Brugarolas, Qing Zhang. BBOX1 is a novel tumor suppressor in kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2600.