CHD4-induced up-regulation of ERα activity contributes to breast cancer progression.
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ABSTRACT:
SUBMITTER: Sattout A
PROVIDER: S-EPMC10825269 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
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CHD4-induced up-regulation of ERα activity contributes to breast cancer progression.
Sattout Aman A Yu Xiaomin X Sun Zhuo Z Li Yanan Y Li Yulin Y Li Shujing S Huo Wei W Wu Huijian H
Genes & diseases 20230915 3
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Project description:Recruitment of RNA polymerase II to hypoxia-inducible factor (HIF) target genes under normoxia is a prerequisite for HIF-mediated transactivation. However, the underlying mechanism of this recruitment remains unknown. Here we report that chromodomain helicase DNA-binding protein 4 (CHD4) physically interacts with α and β subunits of HIF1 and HIF2 and enhances HIF-driven transcriptional programs to promote breast cancer progression. Loss of HIF1/2α abolished CHD4-mediated breast tumor growth in mice. In breast cancer cells under normoxia, CHD4 enrichment at HIF target gene promoters increased RNA polymerase II loading through p300. Hypoxia further promoted CHD4 binding to the chromatin via HIF1/2α, where CHD4 in turn enhanced recruitment of HIF1α, leading to HIF target gene transcription. CHD4 was upregulated and correlated with HIF target gene expression in human breast tumors; upregulation of CHD4 and other known HIF coactivators in human breast tumors was mutually exclusive. Furthermore, CHD4 was associated with poor overall survival of patients with breast cancer. Collectively, these findings reveal a new fundamental mechanism of HIF regulation in breast cancer, which has clinical relevance. SIGNIFICANCE: This study identifies CHD4 as a HIF coactivator and elucidates the fundamental mechanism underlying CHD4-mediated HIF transactivation in breast tumors.
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Project description:The estrogen receptor-alpha (ERα) is used as a predictive marker for anti-estrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ERα can be targeted at the receptor level using the receptor modulator tamoxifen or by the pure anti-estrogen fulvestrant. The role of the second ER, ER-beta (ERβ), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ERα+/ERβ+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ERα-/ERβ+ breast cancer. Here, we report that fulvestrant up-regulated ERβ in ERα+/ERβ+ breast cancer and in triple negative ERβ+ breast cancers (ERα-/ERβ+). In ERα+/ERβ+ breast cancer, a combination therapy of tamoxifen and fulvestrant significantly reduced tumor growth compared to either treatment alone both in vivo and in vitro. In ERα-/ERβ+ breast cancer fulvestrant had potent effects on cancer growth, in vivo as well as in vitro, and this effect was dependent on intrinsically expressed levels of ERβ. The role of ERβ was further confirmed in cells where ERβ was knocked-in or knocked-down. Inhibition of DNA methyltransferase (DNMT) increased the levels of ERβ and fulvestrant exerted similar potency on DNMT activity as the DNMT inhibitor decitabine. We conclude that fulvestrant may have therapeutic potential in additional groups of breast cancer patients; i) in ERα+/ERβ+ breast cancer where fulvestrant synergizes with tamoxifen and ii) in triple negative/ERβ+ breast cancer patients, a subgroup of breast cancer patients with poor prognosis.
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Project description:Breast cancer has the highest incidence and mortality in women worldwide. There are 70% of breast cancers considered as estrogen receptor α (ERα) positive. Therefore, the ERα-targeted therapy has become one of the most effective solution for patients with breast cancer. Whereas a better understanding of ERα regulation is critical to shape evolutional treatments for breast cancer. By exploring the regulatory mechanisms of ERα at levels of post-translational modifications, we identified the deubiquitinase USP15 as a novel protector for preventing ERα degradation and a critical driver for breast cancer progression. Specifically, we demonstrated that USP15 promoted the proliferation of ERα+, but not ERα- breast cancer, in vivo and in vitro. Meanwhile, USP15 knockdown notably enhanced the antitumor activities of tamoxifen on breast cancer cells. Importantly, USP15 knockdown induced the downregulation of ERα protein via promoting its K48-linked ubiquitination, which is required for proliferative inhibition of breast cancer cells. These findings not only provide a novel treatment for overcoming resistance to endocrine therapy, but also represent a therapeutic strategy on ERα degradation by targeting USP15-ERα axis.
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Project description:Estrogen receptor α (ERα) is the most common clinical marker used for breast cancer prognosis and the classification of breast cancer subtypes. Clinically, patients with estrogen receptor-positive breast cancer can receive endocrine therapy. However, resistance to endocrine therapy has become an urgent clinical problem. A large number of previous studies have proven that posttranslational modification of the estrogen receptor is significantly related to endocrine therapy resistance. RNF2 is a member of the RING finger protein family that functions as an E3 ubiquitin ligase. Several studies have clarified that RNF2 is a critical regulator of ERα transcriptional regulation. In our current study, we identified RNF2 as an important posttranslational modification regulator of the estrogen receptor. RNF2 depletion inhibited breast cancer cell progression and ERα signaling activity. TCGA data analysis indicated that RNF2 was elevated in breast malignancies, while RNF2 depletion could drastically inhibit estrogen response gene expression on a whole-genome scale. TCGA data analysis revealed that RNF2 was positively correlated with ERα target gene expression. Further mechanistic studies showed that RNF2 was mainly localized in the nucleus and associated with ERα. The association increased ERα stability by inhibiting ERα K48-linked polyubiquitination. In conclusion, our study implicates nongenomic regulation by RNF2 on ERα protein stability and suggests that targeting RNF2 could be a promising strategy for breast cancer treatments.
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Project description:Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ERα signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ERα positive patients. USP1 depletion inhibited breast cancer cell progression and ERα signaling activity. Immuno-precipitation assays indicate that USP1 associates with ERα and promotes its stability possibly via inhibiting ERα K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.
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Project description:ERα positive breast cancer accounts for 70% of breast malignancies. Compared with ERα negative types, ERα positive breast cancer could be effective controlled by endocrine therapy. However, more than half of the patients will develop endocrine resistance, making it an important clinical issue for breast cancer therapy. Endocrine resistance might be caused by multiple alternations, including the components of ERα signaling, during tumor progression. Thus, it is urgent and necessary to uncover the molecular mechanisms that controls ERα expression and stability to improve breast cancer therapeutics. In our current study, we identifies that the ubiquitin ligase RNF181 stabilizes ERα and facilitates breast cancer progression. The expression of RNF181 is correlated with ERα level in human breast tumors and relates to poor survival in endocrine-treated patients. RNF181 depletion inhibits breast cancer progression in vivo and in vitro, reduces ERα protein level and its target gene expression, such as PS2 and GREB1. Unbiased RNA sequencing analysis indicates RNF181 is necessary for ERα signature gene expression in whole genomic level. Immuno-precipitation assays indicate that RNF181 associates with ERα and promotes its stability possibly via inducing ERα K63-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by RNF181 via stabilizing ERα protein controls ERα target gene expression linked to breast cancer progression.
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Project description:The over-activation of ERα signaling is regarded as the major driver for luminal breast cancers, which could be effective controlled via selective estrogen receptor modulators (SERM), such as tamoxifen. The endocrine resistance is still a challenge for breast cancer treatment, while recently studies implicate the post-translational modification on ERα play important roles in endocrine resistance. The stability of ERα protein and ERα transcriptome are subject to a balance between E3 ubiquitin ligases and deubiquitinases. Through deubiquitinases siRNA library screening, we discover PSMD14 as a critical deubiquitinase for ERα signaling and breast cancer progression. PSMD14 could facilitate breast cancer progression through ERα signaling in vitro and in vivo, while pharmaceutical inhibition of PSMD14 via Thiolutin could block the tumorigenesis in breast cancer. In endocrine resistant models, PSMD14 inhibition could de-stabilize the resistant form of ERα (Y537S) and restore tamoxifen sensitivity. Molecular studies reveal that PSMD14 could inhibition K48-linked poly-ubiquitination on ERα, facilitate ERα transcriptome. Interestingly, ChIP assay shows that ERα could bind to the promoter region of PSMD14 and facilitate its gene transcription, which indicates PSMD14 is both the upstream modulator and downstream target for ERα signaling in breast cancer. In general, we identified a novel positive feedback loop between PSMD14 and ERα signaling in breast cancer progression, while blockade of PSMD14 could be a plausible strategy for luminal breast cancer.
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