Targeting the E3 ubiquitin ligase PJA1 enhances tumor-suppressing TGFβ signaling

Authors

Jian Chen, University of Texas MD Anderson Cancer Center
Abhisek Mitra, Pfizer Inc.
Shulin Li, University of Texas MD Anderson Cancer Center
Shumei Song, University of Texas MD Anderson Cancer Center
Bao Ngoc Nguyen, The George Washington University
Jiun Sheng Chen, University of Texas MD Anderson Cancer Center
Ji Hyun Shin, University of Texas MD Anderson Cancer Center
Nancy R. Gough, The George Washington University
Paul Lin, The George Washington University
Vincent Obias, The George Washington University
Aiwu Ruth He, Georgetown Lombardi Comprehensive Cancer Center
Zhixing Yao, Howard University
Tathiane M. Malta, Henry Ford Hospital
Houtan Noushmehr, Henry Ford Hospital
Patricia S. Latham, The George Washington University
Xiaoping Su, University of Texas MD Anderson Cancer Center
Asif Rashid, University of Texas MD Anderson Cancer Center
Bibhuti Mishra, The George Washington University
Ray Chang Wu, The George Washington University
Lopa Mishra, The George Washington University

Document Type

Journal Article

Publication Date

5-1-2020

Journal

Cancer Research

Volume

80

Issue

9

DOI

10.1158/0008-5472.CAN-19-3116

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.

APA Citation

Chen, J., Mitra, A., Li, S., Song, S., Nguyen, B., Chen, J., Shin, J., Gough, N., Lin, P., Obias, V., He, A., Yao, Z., Malta, T., Noushmehr, H., Latham, P., Su, X., Rashid, A., Mishra, B., Wu, R., & Mishra, L. (2020). Targeting the E3 ubiquitin ligase PJA1 enhances tumor-suppressing TGFβ signaling. Cancer Research, 80 (9). http://dx.doi.org/10.1158/0008-5472.CAN-19-3116