DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer

Abstract

The gene encoding ‘deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library-based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2. MSI2 directly interacted with DBC2, and this interaction promoted MSI2 polyubiquitination and proteasomal degradation in breast cancer cells. Overexpression and knockdown experiments demonstrated that DBC2 suppressed MSI2-associated oncogenic functions and induced apoptosis. Immunohistochemistry analysis of a breast cancer tissue microarray revealed that DBC2 and MSI2 protein levels are inversely correlated in both normal breast tissues and breast cancer tissues. Taken together, these findings provide evidence that DBC2 suppresses tumorigenesis in breast cancer by ubiquitinating MSI2.

Structural Insight into the Recognition of r(UAG) by Musashi-1 RBD2, and Construction of a Model of Musashi-1 RBD1-2 Bound to the Minimum Target RNA

“…Msi1 and Msi2 are shown to be associated with tumor initiation, progression, and drug resistance [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 25 , 26 , 36 , 37 , 38 , 39 ]. Importantly, downregulation of Msi1 and Msi2 proteins in tumors results in reduction of their tumorigenic growth [ 40 , 41 , 42 ]. Thus, Msi1 and Msi2 have been receiving increasing attention in the field of medicine.…”

Knockdown of Musashi RNA Binding Proteins Decreases Radioresistance but Enhances Cell Motility and Invasion in Triple-Negative Breast Cancer

“…In breast cancer, some controversy remains. Some studies identify both MSI-1 and MSI-2 as potential therapeutic targets: MSI-1 has been described to enhance BCSC characteristics through proteasome subunit expression regulation [16], and anti-tumor effects subsequent to MSI-2 targeting have been shown in breast cancer [17]. Another investigation agrees and hypothesizes that MSI-1 and MSI-2 may be suitable targets for therapy [18].…”

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

“…Depletion of RhoBTB cooperates with Yki in a Drosophila epithelial transformation model RhoBTB proteins perform a variety of molecular functions and can target proteins for proteasomal degradation (Choi et al 2016). To study whether RhoBTB activity can regulate the Hippo pathway, we used a Drosophila epithelial tumor model (Song et al 2017) which allows the spatio-temporally controlled expression of transgenes.…”