2. Academic Validation
  3. Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition of breast cancer cells

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

  • Cell Mol Life Sci. 2023 Jan 17;80(2):43. doi: 10.1007/s00018-022-04672-w.
Jing Zhang 1 2,  Maarten van Dinther 1 2,  Midory Thorikay 1 2,  Babak Mousavi Gourabi 3,  Boudewijn P T Kruithof 2 4,  Peter Ten Dijke 5 6
Affiliations

Affiliations

  • 1 Oncode Institute, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
  • 2 Department of Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
  • 3 Department of Anatomy and Embryology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
  • 4 HARTZ, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
  • 5 Oncode Institute, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. [email protected].
  • 6 Department of Cell Chemical Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands. [email protected].
PMID: 36646950 DOI: 10.1007/s00018-022-04672-w
Abstract

Ubiquitin-Specific Protease (USP)19 is a deubiquitinating Enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-β signaling by directly interacting with TGF-β type I receptor (TβRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TβRI in the ER. By decreasing cell surface TβRI levels, USP19-ER inhibits TGF-β/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-β-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast Cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast Cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast Cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast Cancer.

Keywords

Alternative spliced isoform; Breast cancer; Epithelial–mesenchymal transition; Herboxidiene; Transforming growth factor-β; USP19.

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