BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer

Abstract

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2. As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex–restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

“…Mounting evidence supports that LSD1 is overexpressed in many subtypes of BC and promotes their proliferation (Pollock et al, 2012;Yang et al, 2018d;Xu et al, 2019;Wang et al, 2022), differentiation (Wu et al, 2013;Zhang et al, 2013;Ji et al, 2021), metastasis (Li et al, 2011;Qiu et al, 2018;Zheng et al, 2018;Hu et al, 2019;Gong et al, 2021), and drug resistance (Bennani-Baiti, 2012;Verigos et al, 2019;Zhou et al, 2021a;Liu et al, 2022), which makes LSD1 become a promising target for BC therapy. But the detailed mechanisms of the LSD1 in BC progression are unclear and more potential anti-tumor pathways or downstream genes are yet to clarify due to the heterogeneity of varieties of BC subtypes.…”

“…Drug resistance is one of the major causes that leads to distant metastasis, poor prognosis, and death of BC (Wen et al, 2020). LSD1 is widely involved in the resistance to chemotherapy (Kim et al, 2013;Boulding et al, 2018;Verigos et al, 2019;Sobczak et al, 2022), hormone therapy (Bennani-Baiti, 2012;Cortez et al, 2012;Benedetti et al, 2019;Sukocheva et al, 2020), immunotherapy (Qin et al, 2019;Tu et al, 2020), and targeted therapy (Strachowska et al, 2021;Liu et al, 2022) of BC (Table 3). Briefly, LSD1 promotes chemoresistance via functioning as a coactivator through interacting with different ligand proteins (Kim et al, 2013;Boulding et al, 2018;Verigos et al, 2019;Strachowska et al, 2021).…”

“…It mediates resistance to hormone therapy via activating ER transcriptional activity (Cortez et al, 2012;Benedetti et al, 2019). In addition, LSD1 is also involved in resistance to PD-1 antibody treatment and BRD4 inhibitors via its transcriptional inhibitory activity against multiple oncogenes (Qin et al, 2019;Tu et al, 2020;Liu et al, 2022).…”

Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

“…BRD4 associates with the repressive complex LSD1/NuRD1 and occupies H3K4me1 defined SEs. BRD4/LSD1/NuRD complex then represses the activation of drug-resistant genes such as WNT4 , LRP5 , BRAF , GNA13 , and PDPK1 in breast cancer cells [ 74 ]. During long-term treatment with JQ1, the overexpressed PELI1 E3 ligase degrades LSD1, thus decommissioning the BRD4/LSD1/NuRD1 complex.…”

“…During long-term treatment with JQ1, the overexpressed PELI1 E3 ligase degrades LSD1, thus decommissioning the BRD4/LSD1/NuRD1 complex. This activates GNA13 and PDPK1 expression leading to drug resistance in breast cancer [ 74 ]. Combined treatment of BRD4 inhibitor and PELI1 inhibitor (BBT-401) may be effective in treating breast cancer.…”