Role of steroid receptor and coregulator mutations in hormone-dependent cancers

Groner, Anna C.; Brown, Myles

doi:10.1172/jci88885

Cited by 45 publications

(26 citation statements)

References 144 publications

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“…key nodes of thousands of pathways. Coregulators were among master genes (20). In this study, we explored the key role of the ER co-regulator PELP1 in GC oncogenesis and its possible underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

Yan

Sun

et al. 2020

Front. Oncol.

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Background: Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1), a co-activator of estrogen receptors alpha, was confirmed to be directly associated with the oncogenic process of multiple cancers, especially hormone-dependent cancers. The purpose of our research was to explore the biological function, clinical significance, and therapeutic targeted value of PELP1 in gastric cancer (GC). Methods: The expression status of PELP1 in GC cell lines or tissues was analyzed through bioinformatics data mining. Thirty-six GC tissue chip was applied to demonstrate the results of bioinformatics data mining assayed by immunohistochemical method. The expression status of PELP1 in GC cell lines was also analyzed using western blot. Correlation analysis between PELP1 expression and clinicopathological parameter was performed. Kaplan-Meier survival analysis was applied to analyze the relationship between PELP1 expression and total survival time. Three pairs of siRNA were designed to silence the expression of PELP1 in GC. After PELP1 was silenced by siRNA or activated by saRNA, the growth, plate colony formation, migration and invasion ability of the GC cell or normal gastric epithelium cell line was tested in vitro. Cell cycle was tested by flow cytometry. Nude mice xenograft experiment was performed after PELP1 was silenced. The downstream molecular pathway regulated by PELP1 was explored. Molecular docking tool was applied to combine chlorpromazine with PELP1. The inhibitory effect of chlorpromazine in GC was assayed, then it was tested whether PELP1 was a therapeutic target of chlorpromazine in GC. Results: PELP1 expression was elevated in GC cell lines and clinical GC tissue samples. PELP1 silence by siRNA compromised the malignant traits of GC. PELP1 expression positively correlated with tumor invasion depth, lymph node metastasis, tissue grade, TNM stage, but had no correlation with patient age, sex, tumor size, and tumor numbers. Kaplan-Meier survival analysis revealed high PELP1 expression had a shorter survival period in GC patients after follow-up. Q-PCR and western blot revealed PELP1 suppression in GC decreased expression of the c-Src-PI3K-ERK pathway. It was also implied that chlorpromazine (CPZ) can inhibit the malignant traits of GC and downregulate the expression of PELP1. Yan et al. PELP1 Is an Oncogene in Gastric Cancer Conclusions: In a word, PELP1 is an oncogene in gastric cancer and c-Src-PI3K-ERK pathway activation may be responsible for its tumorigenesis, PELP1 may be a potential therapeutic target of chlorpromazine in GC.

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Section: Discussionmentioning

confidence: 99%

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

Yan

Sun

et al. 2020

Front. Oncol.

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“…The activation function 2 (AF2) domai n located in the LBD is involved in the interaction between AR and co-regulators containing the LXXLL motif [12]. Interestingly, point mutations mapped to the LBD have been found and are involved with resistance to hormone treatment in prostate cancer [15,16]. In this case, the interplay between these domains exerts AR transcription and epigenetic functions.…”

Section: Functions Of Ar In Prostate Cancer: Aberrant Ar Activation Imentioning

confidence: 99%

“…Thus, multiple histone modification patterns determine the activity of the genomic regions associated with histones. In prostate cancer, deregulated AR interaction with its coregulators in the nucleus is frequently observed [11,15]; these interactions with coregulators and histone-modifying enzymes provoke AR-dependent epigenetic regulation [8,11]. AR enhancers are characterized by the presence of H3K4me1, H3K27ac, and H2A.Zac, which activate AR-enhancer function of RNA transcription [49].…”

Section: Classification Of Epigenetic Regulationsmentioning

confidence: 99%

Epigenetic Regulation by Androgen Receptor in Prostate Cancer

Takayama¹

2018

obm genet

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Prostate cancer is the most common cancer among men in the world. Androgen receptor (AR), acting as a nuclear receptor, facilitates ligand-dependent transcriptional activation in the nucleus. Androgen deprivation therapy (ADT) is used for the treatment of advanced prostate cancer because androgen and AR signaling drive prostate tumor growth and antiapoptotic function. Resistance to ADT in most tumors develops quickly; thus, AR continues to be active in relapsed tumors called castration-resistant prostate cancer (CRPC). Therefore, it is important to investigate the transcriptional mechanisms of AR and its downstream signaling. Recent studies have shown the central role of chromatin structure and histone modifications in AR-mediated gene regulation. Furthermore, AR functions through interaction with several tissue-specific transcription factors including forkhead box protein A1 (FOXA1). Interestingly, non-coding RNAs, mainly classified as long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs), modulate epigenetic status to promote AR function directly or indirectly and have central roles in prostate cancer progression. This review focuses on the involvement of AR in epigenetic regulation of the development and progression of prostate cancer.

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“…Although the pattern of formation of heterodimers with ER variants remains unclear, it is suggested that the heterodimers may regulate a different set of genes than the homodimers. Recruitment of the dimer, along with co-regulators, known as nuclear receptor co-repressors (NCORs) and nuclear receptor co -activators (NCOAs), is required to exert transcriptional activity of ER dimers on target genes [ 18 ]. The PPIs between ER and its coregulators can be predicted using the in silico Search Tool for Retrieval of Interacting Genes and proteins (STRING) [ 19 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Exploring Protein–Protein Interaction in the Study of Hormone-Dependent Cancers

Miki

Iwabuchi

Ono

et al. 2018

IJMS

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Estrogen receptors promote target gene transcription when they form a dimer, in which two identical (homodimer) or different (heterodimer) proteins are bound to each other. In hormone-dependent cancers, hormone receptor dimerization plays pivotal roles, not only in the pathogenesis or development of the tumors, but also in the development of therapeutic resistance. Protein–protein interactions (PPIs), including dimerization and complex formation, have been also well-known to be required for proteins to exert their functions. The methods which could detect PPIs are genetic engineering (i.e., resonance energy transfer) and/or antibody technology (i.e., co-immunoprecipitation) using cultured cells. In addition, visualization of the target proteins in tissues can be performed using antigen–antibody reactions, as in immunohistochemistry. Furthermore, development of microscopic techniques (i.e., electron microscopy and confocal laser microscopy) has made it possible to visualize intracellular and/or intranuclear organelles. We have recently reported the visualization of estrogen receptor dimers in breast cancer tissues by using the in situ proximity ligation assay (PLA). PLA was developed along the lines of antibody technology development, and this assay has made it possible to visualize PPIs in archival tissue specimens. Localization of PPI in organelles has also become possible using super-resolution microscopes exceeding the resolution limit of conventional microscopes. Therefore, in this review, we summarize the methodologies used for studying PPIs in both cells and tissues, and review the recently reported studies on PPIs of hormones.

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Role of steroid receptor and coregulator mutations in hormone-dependent cancers

Cited by 45 publications

References 144 publications

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

PELP1 Suppression Inhibits Gastric Cancer Through Downregulation of c-Src-PI3K-ERK Pathway

Epigenetic Regulation by Androgen Receptor in Prostate Cancer

Exploring Protein–Protein Interaction in the Study of Hormone-Dependent Cancers

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