USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Abstract

Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial–mesenchymal transition of breast cancer cells

“…Interestingly, USP19-ER was shown to negatively regulate the proliferation and migration of clear cell renal cell carcinoma (ccRCC) by suppressing ERK map kinase activation [ 50 ]. In another study, overexpression of USP19-ER was found to increase breast cancer cell migration and invasion, which was dependent on its catalytic activity [ 51 ]. After the deubiquitylation of LRP6 by USP19, Wnt signaling was increased, which induced cell migration and invasion [ 51 ].…”

“…In another study, overexpression of USP19-ER was found to increase breast cancer cell migration and invasion, which was dependent on its catalytic activity [ 51 ]. After the deubiquitylation of LRP6 by USP19, Wnt signaling was increased, which induced cell migration and invasion [ 51 ]. In the same study, knockdown of total USP19 inhibited MDA-MB-231 cell migration [ 51 ]; this is consistent with the finding that the depletion of USP19-CY, which is the major isoform in MDA-MB-231 cells, also inhibited cell migration.…”

Emerging Role of Ubiquitin-Specific Protease 19 in Oncogenesis and Cancer Development

“…Opposite to the role of USP19 as a tumor suppressor, recent work has also established that antagonism of USP19 expression conferred a prominent antiproliferative and antitumorigenic response in diverse neoplasms: Ewing sarcoma, gastric, breast and colorectal cancers ( Gierisch et al, 2019 ; Dong et al, 2020 ; Rossi et al, 2021 ; Zhu et al, 2021 ), suggesting pro-tumorigenic roles in these tissues.…”

“…Similarly, our group analyzed USP19 clinical significance in breast cancer ( Rossi et al, 2021 ). We demonstrated that USP19 positively regulates breast tumor cells migration and invasion in vitro , and that genetic silencing reduces cells motility, whereas its overexpression increases migratory and invasive capabilities—dependent on USP19’s catalytic activity and ER localization.…”

The BA-BCS 2021: An Initial “Trial” for Integrating Basic Science and Medical Progress on Breast Cancer in a Latin-American Country

“…The PhD student Andrés Elia reported a new trial conducted by Dr. C. Lanari (IBYME-CONICET, Buenos Aires, Argentina) using the antiprogestin mifepristone in selected breast carcinomas with higher levels of isoform A than isoform B of PR. Finally, Dr. Fabiana Rossi, from Dr. M. Rossi Lab, at Austral University, Pilar, Argentina, showed promising pre-clinical data on the use of ubiquitin regulators as novel therapeutic targets [ 50 ].…”