Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1
Leiming Wang, … , Sophia Y. Tsai, Ming-Jer Tsai
Leiming Wang, … , Sophia Y. Tsai, Ming-Jer Tsai
Published December 24, 2019
Citation Information: J Clin Invest. 2020;130(4):1782-1792. https://doi.org/10.1172/JCI126327.
View: Text | PDF
Research Article Oncology

Small molecule JQ1 promotes prostate cancer invasion via BET-independent inactivation of FOXA1

Abstract

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein–independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

Authors

Leiming Wang, Mafei Xu, Chung-Yang Kao, Sophia Y. Tsai, Ming-Jer Tsai

×

Figure 1

JQ1 promotes invasion of prostate cancer cells.

Options: View larger image (or click on image) Download as PowerPoint
JQ1 promotes invasion of prostate cancer cells. (A) Representative image...
(A) Representative images of cell morphology 2 days after 200 nM JQ1 treatment. Scale bars: 50 μm. (B) Cell invasion was measured on the indicated days after 200 nM JQ1 treatment. Representative images of invasion are shown. Scale bars: 200 μm. n = 3 per group. *P < 0.05 and ***P < 0.001, by 1-way ANOVA. (C) Cell invasion was measured 3 days after 200 nM JQ1 treatment. Representative images of invasion are shown. Scale bars: 200 μm. n = 3 per group. ***P < 0.001, by Student’s t test. abl, LNCaP-abl cells. (D) Cell invasion was measured 3 days after treatment with 200 nM of the indicated inhibitor. Representative images of invasion are shown. Scale bars: 200 μm. n = 3 per group. P > 0.05 (NS), *P < 0.05, **P < 0.01, and ***P < 0.001 versus DMSO, by 1-way ANOVA. (E) 22Rv1-Luc cells were injected into SCID mice via the tail vein. JQ1 (10 mg/kg) was given daily by i.p. injection, and images were taken 7 weeks later. Metastatic sites with luciferase signal in different tissues were stained with an AR antibody. Representative images of AR staining are shown. Scale bars: 400 μm. (F) Probasin-Cre Pten-null mice of approximately 18 weeks of age were given 10 mg/kg JQ1 for 7 weeks. Draining lumbar lymph nodes were collected for AR immunohistochemical staining. The percentage of cancer-involved lymph nodes (AR staining–positive lymph nodes/total collected lymph nodes) is shown. (G) Representative AR staining in lymph nodes. Scale bars: 50 μm. (H) Quantitation of the percentage of AR-positive cells in lymph nodes. n = 8–9 per group. **P < 0.01, by Student’s t test.