Crosstalk Between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF

Kum Hee Noh; Ae Jin Jeong; Haeri Lee; Song-Hee Lee; Eunhee Yi; Pahn-Shick Chang; Cheol Kwak; Sang-Kyu Ye

doi:10.3390/cancers12051083

Crosstalk Between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF

Cancers (Basel). 2020 Apr 27;12(5):1083. doi: 10.3390/cancers12051083.

Authors

Kum Hee Noh^{1

2}, Ae Jin Jeong^{1

2}, Haeri Lee^{1

2}, Song-Hee Lee^{1

2}, Eunhee Yi¹, Pahn-Shick Chang^{3

4

5}, Cheol Kwak^{6

7}, Sang-Kyu Ye^{1

2

8

9}

Affiliations

¹ Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
² Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul 03080, Korea.
³ Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea.
⁴ Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Korea.
⁵ Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea.
⁶ Department of Urology, Seoul National University Hospital, Seoul 03080, Korea.
⁷ Department of Urology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Korea.
⁸ Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
⁹ Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul 03080, Korea.

Abstract

Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs-STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.

Keywords: STAT3; promyelocytic leukemia zinc finger; prostate cancer; tumor-associated fibroblast; tumor-suppressor gene.