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 +/-), 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.
Highlights
The incidence of hepatocellular carcinoma (HCC) in the United States has increased three- to four-fold in recent years, and overall 5-year survival rates are only 11% [1, 2]
Our results indicated that PJA1 functions as a tumor-promoting E3 ubiquitin ligase by inhibiting SMAD3/b2SP-regulated genes and suggested that PJA1 represents a potentially useful therapeutic target in HCC associated with impaired TGFb signaling
Following up on our previous work showing that PJA1 interacted with b2SP and mediated both b2SP and SMAD3 ubiquitination [29], and that a TGFb pathway mediated by SMAD3/b2SP promotes tumor-suppressing gene expression [18], we focused on HCC and investigated whether PJA1 functioned as a tumor promoter
Summary
The incidence of hepatocellular carcinoma (HCC) in the United States has increased three- to four-fold in recent years, and overall 5-year survival rates are only 11% [1, 2]. Liver is a regenerative organ with multiple regions in a lobule containing stem cells and niches regulating regeneration [7]. The TGFb/SMAD pathway is a key regulator of liver stem cells (LSC) and liver regeneration [8,9,10,11,12,13]. Some forms of HCC have characteristics of cancer stem cells [14] and may arise through transformation of cells in the LSC population. Mechanistic insight into the pathways that drive stem cell transformation could lead to the development or identification of targeted therapeutics for these cancers. We observed that expression patterns of genes encoding components of this complex pathway are decreased in HCCs ($30%–40% of HCCs), suggesting an inhibitory role of TGFb in cancer stem cell transformation. An inhibitory role for TGFb in this process is consistent with TGFb–deficient mouse models of HCC [16,17,18]
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