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Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling.
- Source :
-
Cancer research [Cancer Res] 2020 May 01; Vol. 80 (9), pp. 1819-1832. Date of Electronic Publication: 2020 Mar 03. - Publication Year :
- 2020
-
Abstract
- RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 ( Smad3 <superscript>+/-</superscript> ), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Animals
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Cell Proliferation drug effects
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Down-Regulation
Gene Deletion
Gene Expression Regulation
Gene Knockdown Techniques
Gene Silencing
Heterografts
Humans
Liver Neoplasms genetics
Liver Neoplasms pathology
Mice
Mice, Nude
Neoplastic Stem Cells
Oleanolic Acid analogs & derivatives
Oleanolic Acid pharmacology
Phosphorylation
RNA, Small Interfering
Smad Proteins metabolism
Smad2 Protein metabolism
Smad3 Protein deficiency
Smad3 Protein genetics
Spectrin genetics
Spectrin metabolism
Stem Cells pathology
Transforming Growth Factor beta genetics
Transforming Growth Factor beta1 metabolism
Ubiquitin-Protein Ligases antagonists & inhibitors
Ubiquitin-Protein Ligases genetics
Ubiquitination
Up-Regulation
Exome Sequencing
Carcinoma, Hepatocellular metabolism
Liver Neoplasms metabolism
Smad3 Protein metabolism
Transforming Growth Factor beta metabolism
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 80
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 32127355
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-19-3116