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FBXO45 is a potential therapeutic target for cancer therapy.

ABSTRACT: FBXO protein 45 (FBXO45), a substrate-recognition subunit of E3 ligases, has been characterised to have pivotal roles in many human diseases, including nervous system diseases, inflammatory diseases and human malignancies. In this article, we describe the expression of FBXO45 in several types of human tumour specimens and highlight the downstream substrates of FBXO45. Moreover, the biological functions of FBXO45 in the regulation of proliferation, apoptosis, the cell cycle and metastasis are mentioned. Furthermore, we describe that the expression level of FBXO45 is regulated by several upstream factors such as miR-27a, Hey1, m6A and the lncRNA RP11. As FBXO45 has a critical role in tumorigenesis and progression, FBXO45 might be a novel therapeutic target for cancer treatment.

SUBMITTER: Lin M

PROVIDER: S-EPMC7335190 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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FBXO45 is a potential therapeutic target for cancer therapy.

Lin Min M Wang Zhi-Wei ZW Zhu Xueqiong X

Cell death discovery 20200703

FBXO protein 45 (FBXO45), a substrate-recognition subunit of E3 ligases, has been characterised to have pivotal roles in many human diseases, including nervous system diseases, inflammatory diseases and human malignancies. In this article, we describe the expression of FBXO45 in several types of human tumour specimens and highlight the downstream substrates of FBXO45. Moreover, the biological functions of FBXO45 in the regulation of proliferation, apoptosis, the cell cycle and metastasis are men ...[more]

PMID: 32655893

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Project description:Abstract Several endocrine therapy (ET) resistance mechanisms for ER-positive (ER+) breast cancer (BC) have been proposed, including acquired ESR1 (ERα gene) mutations. The two most common ESR1 mutations are Y537S and D538G, which give rise to a constitutively active receptor with reduced affinity for agonists and antagonists. The discovery of new effective therapies remains a significant challenge in treating mutated ER+ BC. In this context, Poly (ADP-ribose) polymerase-1 (PARP-1) has captured considerable interest as a target for therapeutic inhibitors in specific types of cancers. Here, we report that crosstalk between PARP-1 and ERα may represent a novel therapeutic approach for ER+ BC. We have demonstrated that the up-regulation of PARP-1 expression, stimulated by 17-β estradiol (E2), was blocked by treatment with fulvestrant (Ful), a potent ERα antagonist, or ESR1 siRNA in ER+ MCF7 and T47D BC cell models that express both wild type ERα and the Y537S mutation, indicating that ERα regulates the expression of PARP-1. In addition, ERα-mediated transcriptional activity depended on PARP-1 activity in these models, as confirmed by ERα target gene expression and ERE reporter gene analyses +/- niraparib (Nira). Notably, PARP-1 modulates the estrogen-dependent genomic binding of ERα and FoxA1, which play a crucial role in the proliferation of ER+ BC. We also showed that PARP-1 inhibition prevented proliferation and cell cycle activities of ERα WT and ERα Y537S cells upon ERα activation. In vivo, Nira and lasofoxifene (Laso), an ERα antagonist, significantly reduced primary tumor growth versus vehicle, both as single agents and in combination. Moreover, RNA-seq analyses demonstrated the downregulation of ERα signaling in the mammary glands of mice treated with Nira versus Vehicle. Our results provide novel insights into the molecular events through which PARP-1 may serve as a more comprehensive therapeutic approach to target ET BC resistance in women with advanced ER+ BC.

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FBXO45 is a potential therapeutic target for cancer therapy.

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FBXO45 is a potential therapeutic target for cancer therapy.

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