Targets for Renal Carcinoma Growth Control Identified by Screening FOXD1 Cell Proliferation Pathways

Abstract

Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle transition. We hypothesized that the identification of pathways downstream of FOXD1 may define candidates for pharmacological modulation to suppress the G2/M transition in ccRCC. We developed an analysis pipeline that utilizes RNA sequencing, transcription factor binding site analysis, and phenotype validation to identify candidate effectors downstream from FOXD1. Compounds that modulate candidate pathways were tested for their ability to cause growth delay at G2/M. Three targets were identified: FOXM1, PME1, and TMEM167A, which were targeted by compounds FDI-6, AMZ-30, and silibinin, respectively. A 3D ccRCC tumor replica model was used to investigate the effects of these compounds on the growth of primary cells from five patients. While silibinin reduced 3D growth in a subset of tumor replicas, FDI-6 reduced growth in all. This study identifies tractable pathways to target G2/M transition and inhibit ccRCC growth, demonstrates the applicability of these strategies across patient tumor replicas, and provides a platform for individualized patient testing of compounds that inhibit tumor growth.

Mitochondrial DNA methylation is a predictor of immunotherapy response and prognosis in breast cancer: scRNA-seq and bulk-seq data insights

“…A recent study showed that SLBP is indeed involved in breast cancer development and that inhibition of SLBP expression would be a promising therapeutic target for breast cancer ( 64 ). Transmembrane Protein 167A (TMEM167A) is a protein associated with vesicle transport and secretion that regulates the transport of newly synthesized proteins from the ER-Golgi to the cell membrane or other organelles and is also required for glioma growth in human cell xenografts and Drosophila models, and interference with TMEM167A expression impedes a variety of tumor cell proliferation ( 65 , 66 ). Transmembrane Protein 67 (TMEM67) plays a role in the migration of centrioles to the apical membrane and the formation of primary cilia ( 67 ).…”

A comprehensive analysis of the FOX family for predicting kidney renal clear cell carcinoma prognosis and the oncogenic role of FOXG1

“…Previous studies have also demonstrated that FOXA1 and FOXD1 are broadly involved in tumor development as well as mitochondrial metabolism. Silencing FOXA1 or FOXD1 in RCC inhibits tumor growth by inhibiting cell cycle progression [ 31 , 32 ]. Moreover, recent research has indicated that FOXA1 may participate in sunitinib resistance in RCC [ 33 ].…”