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Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

Jian Chen1, Abhisek Mitra2, Shulin Li3

  • 1Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. lmishra@gwu.edu jianchen@mdanderson.org.

Cancer Research
|March 5, 2020
PubMed

Insights

PJA1, an E3 ligase, degrades SMAD3, hindering its tumor-suppressing role in liver cancer. Inhibiting PJA1 may offer a new therapeutic strategy for hepatocellular carcinoma (HCC).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • RING-finger E3 ligases regulate critical cellular processes like inflammation, apoptosis, and cancer.
  • The role of E3 ligases in TGFβ/SMAD signaling, particularly in hepatocellular carcinoma (HCC), remains largely unexplored.
  • SMAD3 and its adaptors are key mediators of TGFβ signaling, crucial for suppressing stem cell-like phenotypes in cancer.

Purpose of the Study:

  • To investigate the role of the E3 ligase PJA1 in TGFβ/SMAD signaling within the context of HCC.
  • To elucidate the mechanism by which PJA1 affects SMAD3 activity and tumor suppression.
  • To evaluate the therapeutic potential of targeting PJA1 in HCC treatment.

Main Methods:

  • Utilized HCC cell lines to examine PJA1's effect on SMAD3 ubiquitination and degradation.
  • Employed SMAD3-deficient mice to assess PJA1's impact on liver stem cell transformation.
  • Conducted gene expression analysis following PJA1 knockdown and TGFβ1 signaling to identify co-regulated genes.
  • Tested the efficacy of the E3 ligase inhibitor RTA405 in HCC cell cultures and xenografts.

Main Results:

  • PJA1 promotes ubiquitination and degradation of phosphorylated SMAD3, thereby impairing SMAD3/β2SP-dependent tumor suppression in HCC cells.
  • Overexpression of PJA1 facilitates liver stem cell transformation in SMAD3-deficient mice.
  • Analysis revealed significant overlap in gene expression patterns regulated by PJA1 knockdown and TGFβ1 signaling, with many genes implicated in cancer.
  • The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and inhibited HCC cell growth in vitro and in vivo.

Conclusions:

  • PJA1 acts as an E3 ligase that negatively regulates the tumor suppressor function of SMAD3 in hepatocellular carcinoma.
  • Targeting PJA1 with inhibitors like RTA405 presents a promising therapeutic avenue for HCC treatment and prevention.
  • These findings reveal a novel regulatory mechanism governing TGFβ's tumor suppressor activity in liver carcinogenesis.

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