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.

Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes

“…JQ1 is a small molecule that binds competitively to bromodomains and inhibits MYC gene transcription by displacing bromodomain 4 (BRD4) ( 156 ), and has the added benefit of reducing PD-L1 expression by tumor cells and APCs ( 157 ) while also directly promoting T cell persistence and effector functions in the TME ( 157 , 158 ). Although JQ1 shows promise in driving tumor responses when used in combination with ACT and ICB ( 158 , 159 ), it has also been shown to activate and promote tumor invasion and metastasis pathways in mouse models of prostate cancer ( 160 ), suggesting further investigation is necessary for optimal application in the clinical setting.…”

Single-cell analysis of localized low- and high-grade prostate cancers

“…Identification of gene regulatory programs shared by high-and low-grade tumors present a strong opportunity to identify biomarkers for patient stratification despite the overwhelming molecular and cellular heterogeneity that exists in prostate cancer. There are several drugs in development targeting FOXA1 and HOXB13 [77][78][79]. Our results suggest that these therapies could potentially benefit patients with high-grade nonmetastatic prostate tumors.…”

GABRQ is Overexpressed and Correlated with Tumor Progression in Breast Cancer

“…J. Chen et al [15] reported that arachidonate lipoxygenase12 could suppress growth and migration of lung cancer cells by suppressing EMT pathway activity. Besides, some other studies have also noted that the activation of the EMT pathway was positively correlated with cancer metastasis, such as colorectal cancer [16] cervical cancer [17,18] and prostate cancer [19].…”