TUSC4 functions as a tumor suppressor by regulating BRCA1’s stability via the E3 ubiquitination pathway

Expression of the tumor suppressor protein BRCA1 is frequently lost in breast cancer patients, and the loss of its expression is associated with disruption of various critical functions in cells and cancer development. In the present study, we demonstrated that microarray analysis of cells with tumor suppressor candidate 4 (TUSC4) knockdown indicated critical changes such as cell cycle, cell death pathways and a global impact to cancer development. More importantly, we observed a clear cluster pattern of TUSC4-knockdown gene profiles with established homologous recombination (HR) repair defect signature. Additionally, TUSC4 protein can physically interact with E3 ligase Herc2 and prevents BRCA1 degradation via ubiquitination pathway. Knockdown of TUSC4 expression enhanced BRCA1 polyubiquitination, leading to BRCA1 protein degradation and a marked reduction in HR repair efficiency. Notably, ectopic expression of TUSC4 effectively suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, knockdown of TUSC4 expression transformed normal mammary epithelial cells and enhanced the sensitivity of U2OS cells to the treatment of poly(ADP-ribose) polymerase inhibitors. Therefore, TUSC4 may act as a bona fide tumor suppressor by regulating BRCA1 protein stability and function in breast cancer. Two groups of samples are included: 1.U2OS-shcontrol 2.U2OS-shTUSC4 knockdown. Gene expression profiles of U2OS-shTUSC4 cells were compared to that of parental U2OS-shcontrol cells.