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Cho Y, Song DG, Kim SN, Kim YK. CARM1 S217 phosphorylation by CDK1 in late G2 phase facilitates mitotic entry. Cell Death Dis 2025; 16:202. [PMID: 40133267 PMCID: PMC11937338 DOI: 10.1038/s41419-025-07533-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 02/15/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025]
Abstract
The coactivator-associated arginine methyltransferase 1 (CARM1) functions as an epigenetic writer, however, its role in mitosis remains poorly understood. In this study, we identified CARM1 as a novel substrate of cyclin-dependent kinase 1 (CDK1) and revealed its novel function as a scaffold that regulates CDK1 stability. During interphase, CARM1 acts as an adaptor in the Cullin-1-mediated CDK1 degradation process, limiting nuclear levels of CDK1. In late G2 phase, the CDK1/Cyclin B1 complex translocates to the nucleus, where it phosphorylates the S217 residue of CARM1. This phosphorylation not only inhibits CARM1's enzymatic activity but also facilitates its translocation to the cytoplasm, leading to the loss of its scaffolding function. Consequently, the CDK1/Cyclin B1 complex resides for longer in the nucleus and initiates mitosis. In addition, depletion or inhibition of CARM1 facilitates entry into mitosis, resulting in accelerated cell growth. Overall, our findings expand the cellular functions of CARM1 beyond its enzymatic activity.
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Affiliation(s)
- Yena Cho
- Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea
- College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Dae-Geun Song
- Natural Products Research Institute, KIST Gangneung, Gangneung, 25451, Republic of Korea
- Natural Product Applied Science, KIST School, University of Science and Technology, Gangneung, 25451, Republic of Korea
| | - Su-Nam Kim
- Natural Products Research Institute, KIST Gangneung, Gangneung, 25451, Republic of Korea
- Natural Product Applied Science, KIST School, University of Science and Technology, Gangneung, 25451, Republic of Korea
| | - Yong Kee Kim
- Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
- College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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2
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Pauss SN, Bates EA, Martinez GJ, Bates ZT, Kipp ZA, Gipson CD, Hinds TD. Steroid receptors and coregulators: Dissemination of sex differences and emerging technologies. J Biol Chem 2025; 301:108363. [PMID: 40023399 DOI: 10.1016/j.jbc.2025.108363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/04/2025] Open
Abstract
Steroid receptors are ligand-induced transcription factors that have broad functions among all living animal species, ranging from control of sex differences, body weight, stress responses, and many others. Their binding to coregulator proteins is regulated by corepressors and coactivators that interchange upon stimulation with a ligand. Coregulator proteins are an imperative and understudied aspect of steroid receptor signaling. Here, we discuss steroid receptor basics from protein domain structures that allow them to interact with coregulators and other proteins, their essential functions as transcription factors, and other elemental protein-protein interactions. We deliberate about the mechanisms that coregulators control in steroid receptor signaling, sex hormone signaling differences, sex hormone treatment in the opposite sex, and how these affect the coregulator and sex steroid receptor complexes. The steroid receptor-coregulator signaling mechanisms are essential built-in components of the mammalian DNA that mediate physiological and everyday functions. Targeting their crosstalk might be useful when imbalances lead to disease. We introduce novel technologies, such as the PamGene PamStation, which make investigating the heterogeneity of the steroid receptor-coregulator complexes and targeting their binding more feasible. This review provides an extensive understanding of steroid receptor-coregulator signaling and how these interactions are intrinsic to many physiological functions that may offer therapeutic advantages.
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Affiliation(s)
- Sally N Pauss
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Evelyn A Bates
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Genesee J Martinez
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Zane T Bates
- Department of Bioengineering, University of Toledo College of Engineering, Toledo, Ohio, USA
| | - Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Cassandra D Gipson
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
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3
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Agnoletto A, Brisken C. Hormone Signaling in Breast Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:279-307. [PMID: 39821031 DOI: 10.1007/978-3-031-70875-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Hormones control normal breast development and function. They also impinge on breast cancer (BC) development and disease progression in direct and indirect ways. The major ovarian hormones, estrogens and progesterone, have long been established as key regulators of mammary gland development in rodents and linked to human disease. However, their roles have been difficult to disentangle because they act on multiple tissues and can act directly and indirectly on different cell types in the breast, and their receptors interact at different levels within the target cell. Estrogens are well-recognized drivers of estrogen receptor-positive (ER+) breast cancers, and the ER is successfully targeted in ER+ disease. The role of progesterone receptor (PR) as a potential target to be activated or inhibited is debated, and androgen receptor (AR) signaling has emerged as a potentially interesting pathway to target on the stage.In this chapter, we discuss hormone signaling in normal breast development and in cancer, with a specific focus on the key sex hormones: estrogen, progesterone, and testosterone. We will highlight the complexities of endocrine control mechanisms at the organismal, tissue, cellular, and molecular levels. As we delve into the mechanisms of action of hormone receptors, their interplay and their context-dependent roles in breast cancer will be discussed. Drawing insights from new preclinical models, we will describe the lessons learned and the current challenges in understanding hormone action in breast cancer.
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Affiliation(s)
- Andrea Agnoletto
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
| | - Cathrin Brisken
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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Xie Z, Tian Y, Guo X, Xie N. The emerging role of CARM1 in cancer. Cell Oncol (Dordr) 2024; 47:1503-1522. [PMID: 38619752 PMCID: PMC11466993 DOI: 10.1007/s13402-024-00943-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2024] [Indexed: 04/16/2024] Open
Abstract
Coactivator-associated arginine methyltransferase 1 (CARM1), pivotal for catalyzing arginine methylation of histone and non-histone proteins, plays a crucial role in developing various cancers. CARM1 was initially recognized as a transcriptional coregulator by orchestrating chromatin remodeling, transcription regulation, mRNA splicing and stability. This diverse functionality contributes to the recruitment of transcription factors that foster malignancies. Going beyond its established involvement in transcriptional control, CARM1-mediated methylation influences a spectrum of biological processes, including the cell cycle, metabolism, autophagy, redox homeostasis, and inflammation. By manipulating these physiological functions, CARM1 becomes essential in critical processes such as tumorigenesis, metastasis, and therapeutic resistance. Consequently, it emerges as a viable target for therapeutic intervention and a possible biomarker for medication response in specific cancer types. This review provides a comprehensive exploration of the various physiological functions of CARM1 in the context of cancer. Furthermore, we discuss potential CARM1-targeting pharmaceutical interventions for cancer therapy.
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Affiliation(s)
- Zizhuo Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yuan Tian
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xiaohan Guo
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Na Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.
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Cho Y, Kim YK. CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence. Redox Biol 2024; 76:103344. [PMID: 39265499 PMCID: PMC11415932 DOI: 10.1016/j.redox.2024.103344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 09/04/2024] [Indexed: 09/14/2024] Open
Abstract
CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating PGC-1α and TFAM expression, while promoting mitochondrial fission through increased DNM1L expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.
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Affiliation(s)
- Yena Cho
- Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea; College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Yong Kee Kim
- Muscle Physiome Research Center and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea; College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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Bacabac M, Liu P, Xu W. Protein Arginine Methyltransferase CARM1 in Human Breast Cancer. Endocrinology 2024; 165:bqae068. [PMID: 38878278 PMCID: PMC11220664 DOI: 10.1210/endocr/bqae068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Indexed: 07/04/2024]
Abstract
Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that deposits asymmetrical dimethylation marks on both histone and nonhistone substrates. The regulatory role of CARM1 in transcription was first identified in estrogen receptor positive (ER+) breast cancer. Since then, the mechanism of CARM1 in activating ER-target genes has been further interrogated. CARM1 is expressed at the highest level in ER negative (ER-) breast cancer and higher expression correlates with poor prognosis, suggesting an oncogenic role of CARM1. Indeed, in ER- breast cancer, CARM1 can promote proliferation and metastasis at least partly through methylation of proteins and activation of oncogenes. In this review, we summarize the mechanisms of transcriptional activation by CARM1 in breast cancer. The methyltransferase activity of CARM1 is important for many of its functions; here, we also highlight the nonenzymatic roles of CARM1. We also cover the biological processes regulated by CARM1 that are often deregulated in cancer and the ways to harness CARM1 in cancer treatment.
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Affiliation(s)
- Megan Bacabac
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
- UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Peng Liu
- UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin–Madison, Madison, WI 53726, USA
| | - Wei Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA
- UW Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA
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Chen C, Ding Y, Huang Q, Zhang C, Zhao Z, Zhou H, Li D, Zhou G. Relationship between arginine methylation and vascular calcification. Cell Signal 2024; 119:111189. [PMID: 38670475 DOI: 10.1016/j.cellsig.2024.111189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/11/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
In patients on maintenance hemodialysis (MHD), vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD), which is the primary cause of death in chronic kidney disease (CKD). The main component of VC in CKD is the vascular smooth muscle cells (VSMCs). VC is an ordered, dynamic activity. Under the stresses of oxidative stress and calcium-‑phosphorus imbalance, VSMCs undergo osteogenic phenotypic transdifferentiation, which promotes the formation of VC. In addition to traditional epigenetics like RNA and DNA control, post-translational modifications have been discovered to be involved in the regulation of VC in recent years. It has been reported that the process of osteoblast differentiation is impacted by catalytic histone or non-histone arginine methylation. Its function in the osteogenic process is comparable to that of VC. Thus, we propose that arginine methylation regulates VC via many signaling pathways, including as NF-B, WNT, AKT/PI3K, TGF-/BMP/SMAD, and IL-6/STAT3. It might also regulate the VC-related calcification regulatory factors, oxidative stress, and endoplasmic reticulum stress. Consequently, we propose that arginine methylation regulates the calcification of the arteries and outline the regulatory mechanisms involved.
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Affiliation(s)
- Chen Chen
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Yuanyuan Ding
- Department of Pain Management, Shengjing Hospital, China Medical University, China
| | - Qun Huang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Chen Zhang
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Zixia Zhao
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Hua Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Detian Li
- Department of Nephrology, Shengjing Hospital, China Medical University, China
| | - Guangyu Zhou
- Department of Nephrology, Shengjing Hospital, China Medical University, China.
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Li K, Shu D, Li H, Lan A, Zhang W, Tan Z, Huang M, Tomasi ML, Jin A, Yu H, Shen M, Liu S. SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer. Cell Death Dis 2024; 15:444. [PMID: 38914552 PMCID: PMC11196642 DOI: 10.1038/s41419-024-06838-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 06/11/2024] [Accepted: 06/14/2024] [Indexed: 06/26/2024]
Abstract
Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.
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MESH Headings
- Humans
- Smad4 Protein/metabolism
- Smad4 Protein/genetics
- Female
- Breast Neoplasms/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/drug therapy
- Signal Transduction/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Receptor, ErbB-2/metabolism
- Receptor, ErbB-2/genetics
- Receptors, Estrogen/metabolism
- Cell Line, Tumor
- Animals
- Tamoxifen/pharmacology
- Tamoxifen/therapeutic use
- Tamoxifen/analogs & derivatives
- Mice
- Antineoplastic Agents, Hormonal/pharmacology
- Antineoplastic Agents, Hormonal/therapeutic use
- Mice, Nude
- Gene Expression Regulation, Neoplastic/drug effects
- Autophagy/drug effects
- ErbB Receptors/metabolism
- ErbB Receptors/genetics
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Affiliation(s)
- Kang Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Dan Shu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Han Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Ailin Lan
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Wenjie Zhang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Zhaofu Tan
- Department of Dermatology and Venereology, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China
| | - Man Huang
- Department of Breast Center, Chongqing University Three Gorges Hospital, Wanzhou, 404000, Chongqing, China
| | - Maria Lauda Tomasi
- Department of Medicine, Cedars-Sinai Medical Center, DAVIS Research Building 3096A, 8700 Beverly Blv, Los Angeles, CA, 90048, USA
| | - Aishun Jin
- Department of Immunology, School of Basic Medical Sciences, Chongqing Medical University, 400010, Chongqing, China
| | - Haochen Yu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
| | - Meiying Shen
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
| | - Shengchun Liu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016, Chongqing, China.
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Itonaga H, Mookhtiar AK, Greenblatt SM, Liu F, Martinez C, Bilbao D, Rains M, Hamard PJ, Sun J, Umeano AC, Duffort S, Chen C, Man N, Mas G, Tottone L, Totiger T, Bradley T, Taylor J, Schürer S, Nimer SD. Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity. Nat Commun 2024; 15:3415. [PMID: 38649367 PMCID: PMC11035800 DOI: 10.1038/s41467-024-47689-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 04/04/2024] [Indexed: 04/25/2024] Open
Abstract
An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells.
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Affiliation(s)
- Hidehiro Itonaga
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Adnan K Mookhtiar
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Sarah M Greenblatt
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- Genomics Institute of the Novartis Research Foundation, San Diego, CA, 92121, USA
| | - Fan Liu
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Concepcion Martinez
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Daniel Bilbao
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Masai Rains
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Pierre-Jacques Hamard
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- Center for Epigenetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Jun Sun
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
- Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Afoma C Umeano
- Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Stephanie Duffort
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Chuan Chen
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Na Man
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Gloria Mas
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Luca Tottone
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Tulasigeri Totiger
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Terrence Bradley
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, 33136, USA
| | - Justin Taylor
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Stephan Schürer
- Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA
| | - Stephen D Nimer
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
- Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
- Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
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10
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VANLIESHOUT TIFFANYL, STOUTH DEREKW, RAZIEE ROZHIN, SRAKA ANNESOPHIEJ, MASOOD HOORIYAA, NG SEANY, MATTINA STEPHANIER, MIKHAIL ANDREWI, MANTA ALEXANDER, LJUBICIC VLADIMIR. Sex-Specific Effect of CARM1 in Skeletal Muscle Adaptations to Exercise. Med Sci Sports Exerc 2024; 56:486-498. [PMID: 37882083 PMCID: PMC11812668 DOI: 10.1249/mss.0000000000003333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023]
Abstract
PURPOSE The purpose of this study was to determine how the intersection of coactivator-associated arginine methyltransferase 1 (CARM1) and biological sex affects skeletal muscle adaptations to chronic physical activity. METHODS Twelve-week-old female (F) and male (M) wild-type (WT) and CARM1 skeletal muscle-specific knockout (mKO) mice were randomly assigned to sedentary (SED) or voluntary wheel running (VWR) experimental groups. For 8 wk, the animals in the VWR cohort had volitional access to running wheels. Subsequently, we performed whole-body functional tests, and 48 h later muscles were harvested for molecular analysis. Western blotting, enzyme activity assays, as well as confocal and transmission electron microscopy were used to examine skeletal muscle biology. RESULTS Our data reveal a sex-dependent reduction in VWR volume caused by muscle-specific ablation of CARM1, as F CARM1 mKO mice performed less chronic, volitional exercise than their WT counterparts. Regardless of VWR output, exercise-induced adaptations in physiological function were similar between experimental groups. A broad panel of protein arginine methyltransferase (PRMT) biology measurements, including markers of arginine methyltransferase expression and activity, were unaffected by VWR, except for CARM1 and PRMT7 protein levels, which decreased and increased with VWR, respectively. Changes in myofiber morphology and mitochondrial protein content showed similar trends among animals. However, a closer examination of transmission electron microscopy images revealed contrasting responses to VWR in CARM1 mKO mice compared with WT littermates, particularly in mitochondrial size and fractional area. CONCLUSIONS The present findings demonstrate that CARM1 mKO reduces daily running volume in F mice, as well as exercise-evoked skeletal muscle mitochondrial plasticity, which indicates that this enzyme plays an essential role in sex-dependent differences in exercise performance and mitochondrial health.
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11
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Romo BA, Karakyriakou B, Cressey L, Brauer BL, Yang H, Warren A, Johnson AL, Kettenbach AN, Miller TW. TRIM33 Is a Co-Regulator of Estrogen Receptor Alpha. Cancers (Basel) 2024; 16:845. [PMID: 38473207 PMCID: PMC10930732 DOI: 10.3390/cancers16050845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/15/2024] [Accepted: 02/17/2024] [Indexed: 03/14/2024] Open
Abstract
Estrogen receptor alpha (ER)-positive breast cancer is responsible for over 60% of breast cancer cases in the U.S. Among patients diagnosed with early-stage ER+ disease, 1/3 will experience recurrence despite treatment with adjuvant endocrine therapy. ER is a nuclear hormone receptor responsible for estrogen-driven tumor growth. ER transcriptional activity is modulated by interactions with coregulators. Dysregulation of the levels of these coregulators is involved in the development of endocrine resistance. To identify ER interactors that modulate transcriptional activity in breast cancer, we utilized biotin ligase proximity profiling of ER interactomes. Mass spectrometry analysis revealed tripartite motif containing 33 (TRIM33) as an estrogen-dependent interactor of ER. shRNA knockdown showed that TRIM33 promoted ER transcriptional activity and estrogen-induced cell growth. Despite its known role as an E3 ubiquitin ligase, TRIM33 increased the stability of endogenous ER in breast cancer cells. TRIM33 offers a novel target for inhibiting estrogen-induced cancer cell growth, particularly in cases of endocrine resistance driven by ER (ESR1) gene amplification or overexpression.
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Affiliation(s)
- Bianca A. Romo
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Barbara Karakyriakou
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Lauren Cressey
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Brooke L. Brauer
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Huijuan Yang
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Alexa Warren
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Anneka L. Johnson
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Arminja N. Kettenbach
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
| | - Todd W. Miller
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03755, USA
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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12
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Zhu Y, Xia T, Chen DQ, Xiong X, Shi L, Zuo Y, Xiao H, Liu L. Promising role of protein arginine methyltransferases in overcoming anti-cancer drug resistance. Drug Resist Updat 2024; 72:101016. [PMID: 37980859 DOI: 10.1016/j.drup.2023.101016] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 10/16/2023] [Accepted: 10/30/2023] [Indexed: 11/21/2023]
Abstract
Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications.
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Affiliation(s)
- Yongxia Zhu
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Tong Xia
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Da-Qian Chen
- Department of Medicine Oncology, Shenzhen Longhua District Central Hospital, Shenzhen 518110, China
| | - Xia Xiong
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China
| | - Lihong Shi
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Yueqi Zuo
- Shaanxi Key Laboratory of Brain Disorders, Institute of Basic Translational Medicine, Xi'an Medical University, Xi'an 710021, China.
| | - Hongtao Xiao
- Department of Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China.
| | - Li Liu
- Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou 646000, China.
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13
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Ma Z, Lyu X, Qin N, Liu H, Zhang M, Lai Y, Dong B, Lu P. Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development. Genes Dis 2023; 10:2383-2392. [PMID: 37554200 PMCID: PMC10404874 DOI: 10.1016/j.gendis.2022.05.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/19/2022] [Accepted: 05/11/2022] [Indexed: 11/26/2022] Open
Abstract
Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.
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Affiliation(s)
- Zhongrui Ma
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Immunology, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Xinxing Lyu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Ning Qin
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Haoyu Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Mengrui Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Yongchao Lai
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Peiyuan Lu
- Medical Research Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
- Department of Immunology, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
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14
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Zheng K, Chen S, Ren Z, Wang Y. Protein arginine methylation in viral infection and antiviral immunity. Int J Biol Sci 2023; 19:5292-5318. [PMID: 37928266 PMCID: PMC10620831 DOI: 10.7150/ijbs.89498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/10/2023] [Indexed: 11/07/2023] Open
Abstract
Protein arginine methyltransferase (PRMT)-mediated arginine methylation is an important post-transcriptional modification that regulates various cellular processes including epigenetic gene regulation, genome stability maintenance, RNA metabolism, and stress-responsive signal transduction. The varying substrates and biological functions of arginine methylation in cancer and neurological diseases have been extensively discussed, providing a rationale for targeting PRMTs in clinical applications. An increasing number of studies have demonstrated an interplay between arginine methylation and viral infections. PRMTs have been found to methylate and regulate several host cell proteins and different functional types of viral proteins, such as viral capsids, mRNA exporters, transcription factors, and latency regulators. This modulation affects their activity, subcellular localization, protein-nucleic acid and protein-protein interactions, ultimately impacting their roles in various virus-associated processes. In this review, we discuss the classification, structure, and regulation of PRMTs and their pleiotropic biological functions through the methylation of histones and non-histones. Additionally, we summarize the broad spectrum of PRMT substrates and explore their intricate effects on various viral infection processes and antiviral innate immunity. Thus, comprehending the regulation of arginine methylation provides a critical foundation for understanding the pathogenesis of viral diseases and uncovering opportunities for antiviral therapy.
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Affiliation(s)
- Kai Zheng
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Siyu Chen
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Zhe Ren
- Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, 510632, China
| | - Yifei Wang
- Institute of Biomedicine, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, 510632, China
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15
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Jin W, Zhang J, Chen X, Yin S, Yu H, Gao F, Yao D. Unraveling the complexity of histone-arginine methyltransferase CARM1 in cancer: From underlying mechanisms to targeted therapeutics. Biochim Biophys Acta Rev Cancer 2023; 1878:188916. [PMID: 37196782 DOI: 10.1016/j.bbcan.2023.188916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/28/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023]
Abstract
Coactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs. Therefore, in this review, we summarize the molecular structure of CARM1 and its key regulatory pathways, as well as further discuss the rapid progress in better understanding of the oncogenic functions of CARM1. Moreover, we further demonstrate several representative targeted CARM1 inhibitors, especially focusing on demonstrating their designing strategies and potential therapeutic applications. Together, these inspiring findings would shed new light on elucidating the underlying mechanisms of CARM1 and provide a clue on discovery of more potent and selective CARM1 inhibitors for the future targeted cancer therapy.
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Affiliation(s)
- Wenke Jin
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China; School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, and State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Jin Zhang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China; School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China
| | - Siwen Yin
- School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Haiyang Yu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, and State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Feng Gao
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
| | - Dahong Yao
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518118, China.
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16
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Kiriyama Y, Nochi H. Regulation of PD-L1 Expression by Nuclear Receptors. Int J Mol Sci 2023; 24:9891. [PMID: 37373038 DOI: 10.3390/ijms24129891] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/04/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
The suppression of excessive immune responses is necessary to prevent injury to the body, but it also allows cancer cells to escape immune responses and proliferate. Programmed cell death 1 (PD-1) is a co-inhibitory molecule that is present on T cells and is the receptor for programmed cell death ligand 1 (PD-L1). The binding of PD-1 to PD-L1 leads to the inhibition of the T cell receptor signaling cascade. PD-L1 has been found to be expressed in many types of cancers, such as lung, ovarian, and breast cancer, as well as glioblastoma. Furthermore, PD-L1 mRNA is widely expressed in normal peripheral tissues including the heart, skeletal muscle, placenta, lungs, thymus, spleen, kidney, and liver. The expression of PD-L1 is upregulated by proinflammatory cytokines and growth factors via a number of transcription factors. In addition, various nuclear receptors, such as androgen receptor, estrogen receptor, peroxisome-proliferator-activated receptor γ, and retinoic-acid-related orphan receptor γ, also regulate the expression of PD-L1. This review will focus on the current knowledge of the regulation of PD-L1 expression by nuclear receptors.
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Affiliation(s)
- Yoshimitsu Kiriyama
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan
- Institute of Neuroscience, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan
| | - Hiromi Nochi
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan
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17
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Hany D, Vafeiadou V, Picard D. CRISPR-Cas9 screen reveals a role of purine synthesis for estrogen receptor α activity and tamoxifen resistance of breast cancer cells. SCIENCE ADVANCES 2023; 9:eadd3685. [PMID: 37172090 PMCID: PMC10181187 DOI: 10.1126/sciadv.add3685] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
In breast cancer, resistance to endocrine therapies that target estrogen receptor α (ERα), such as tamoxifen and fulvestrant, remains a major clinical problem. Whether and how ERα+ breast cancers switch from being estrogen-dependent to estrogen-independent remains unclear. With a genome-wide CRISPR-Cas9 knockout screen, we identified previously unknown biomarkers and potential therapeutic targets of endocrine resistance. We demonstrate that high levels of PAICS, an enzyme involved in the de novo biosynthesis of purines, can shift the balance of ERα activity to be more estrogen-independent and tamoxifen-resistant. We find that this may be due to elevated activities of cAMP-activated protein kinase A and mTOR, kinases known to phosphorylate ERα specifically and to stimulate its activity. Genetic or pharmacological targeting of PAICS sensitizes tamoxifen-resistant cells to tamoxifen. Addition of purines renders them more resistant. On the basis of these findings, we propose the combined targeting of PAICS and ERα as a new, effective, and potentially safe therapeutic regimen.
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Affiliation(s)
- Dina Hany
- Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
- On leave from: Department of Pharmacology and Therapeutics Faculty of Pharmacy, Pharos University in Alexandria, Alexandria 21311, Egypt
| | - Vasiliki Vafeiadou
- Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
| | - Didier Picard
- Département de Biologie Moléculaire et Cellulaire, Université de Genève, Sciences III, Quai Ernest-Ansermet 30, CH - 1211 Genève 4, Switzerland
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18
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Rosenberg L, Liu C, Sharma R, Wood C, Vyhlidal CA, Gaedigk R, Kho AT, Ziniti JP, Celedón JC, Tantisira KG, Weiss ST, McGeachie MJ, Kechris K, Sharma S. Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma. Int J Mol Sci 2023; 24:7727. [PMID: 37175432 PMCID: PMC10178351 DOI: 10.3390/ijms24097727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/14/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA-mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA-mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA-mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.
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Affiliation(s)
- Lynne Rosenberg
- Department of Pediatrics and Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Cuining Liu
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rinku Sharma
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Cheyret Wood
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - Roger Gaedigk
- Children’s Mercy Hospital and Clinics, Kansas City, MO 64108, USA
| | - Alvin T. Kho
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - John P. Ziniti
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Juan C. Celedón
- Division of Pediatric Pulmonary Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Kelan G. Tantisira
- Division of Pediatric Respiratory Medicine, Rady Children’s Hospital, University of California, San Diego, CA 92123, USA
| | - Scott T. Weiss
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Michael J. McGeachie
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Katerina Kechris
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Sunita Sharma
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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19
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Yang FF, Xu XL, Hu T, Liu JQ, Zhou JZ, Ma LY, Liu HM. Lysine-Specific Demethylase 1 Promises to Be a Novel Target in Cancer Drug Resistance: Therapeutic Implications. J Med Chem 2023; 66:4275-4293. [PMID: 37014989 DOI: 10.1021/acs.jmedchem.2c01527] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
Abstract
Chemotherapy, targeted therapy, and immunotherapy are effective against most tumors, but drug resistance remains a barrier to successful treatment. Lysine-specific demethylase 1 (LSD1), a member of histone demethylation modifications, can regulate invasion, metastasis, apoptosis, and immune escape of tumor cells, which are associated with tumorigenesis and tumor progression. Recent studies suggest that LSD1 ablation regulates resensitivity of tumor cells to anticarcinogens containing immune checkpoint inhibitors (ICIs) via multiple upstream and downstream pathways. In this review, we describe the recent findings about LSD1 biology and its role in the development and progression of cancer drug resistance. Further, we summarize LSD1 inhibitors that have a reversal or resensitive effect on drug resistance and discuss the possibility of targeting LSD1 in combination with other agents to surmount resistance.
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Affiliation(s)
- Fei-Fei Yang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Xue-Li Xu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Ting Hu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jian-Quan Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Jin-Zhu Zhou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Li-Ying Ma
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
- Key Laboratory of Cardio-Cerebrovascular Drug, China Meheco Topfond Pharmaceutical Company, Zhumadian 463000, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, School of Pharmaceutical Science and Institute of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China
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20
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Wang W, Spurgeon ME, Pope A, McGregor S, Ward-Shaw E, Gronski E, Lambert PF. Stress keratin 17 and estrogen support viral persistence and modulate the immune environment during cervicovaginal murine papillomavirus infection. Proc Natl Acad Sci U S A 2023; 120:e2214225120. [PMID: 36917668 PMCID: PMC10041145 DOI: 10.1073/pnas.2214225120] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 02/10/2023] [Indexed: 03/16/2023] Open
Abstract
A murine papillomavirus, MmuPV1, infects both cutaneous and mucosal epithelia of laboratory mice and can be used to model high-risk human papillomavirus (HPV) infection and HPV-associated disease. We have shown that estrogen exacerbates papillomavirus-induced cervical disease in HPV-transgenic mice. We have also previously identified stress keratin 17 (K17) as a host factor that supports MmuPV1-induced cutaneous disease. Here, we sought to test the role of estrogen and K17 in MmuPV1 infection and associated disease in the female reproductive tract. We experimentally infected wild-type and K17 knockout (K17KO) mice with MmuPV1 in the female reproductive tract in the presence or absence of exogenous estrogen for 6 mon. We observed that a significantly higher percentage of K17KO mice cleared the virus as opposed to wild-type mice. In estrogen-treated wild-type mice, the MmuPV1 viral copy number was significantly higher compared to untreated mice by as early as 2 wk postinfection, suggesting that estrogen may help facilitate MmuPV1 infection and/or establishment. Consistent with this, viral clearance was not observed in either wild-type or K17KO mice when treated with estrogen. Furthermore, neoplastic disease progression and cervical carcinogenesis were supported by the presence of K17 and exacerbated by estrogen treatment. Subsequent analyses indicated that estrogen treatment induces a systemic immunosuppressive state in MmuPV1-infected animals and that both estrogen and K17 modulate the local intratumoral immune microenvironment within MmuPV1-induced neoplastic lesions. Collectively, these findings suggest that estrogen and K17 act at multiple stages of papillomavirus-induced disease at least in part via immunomodulatory mechanisms.
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Affiliation(s)
- Wei Wang
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Megan E. Spurgeon
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Ali Pope
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Stephanie McGregor
- Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI53705
| | - Ella Ward-Shaw
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Ellery Gronski
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI53705
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21
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Schmiedecke SS, Thagard AS, Edwards SM, Talley RL, Dornisch EM, Damicis JR, McLane M, Burd I, Napolitano PG, Ieronimakis N. Estrogen receptor 1 appears essential for fetal viability in a murine model of premature birth. Am J Reprod Immunol 2023; 89:e13662. [PMID: 36458539 DOI: 10.1111/aji.13662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/21/2022] [Accepted: 11/17/2022] [Indexed: 12/05/2022] Open
Abstract
PROBLEM Protective effects for adult neurological disorders have been attributed to sex hormones. Using a murine model of prematurity, we evaluated the role of estrogen signaling in the process of perinatal brain injury following exposure to intrauterine inflammation. METHOD OF STUDY Intrauterine lipopolysaccharide (LPS) was used to invoke preterm labor and fetal neuroinflammation. Fetal brains were analyzed for changes in Esr1, Esr2 and Cyp19. Dams heterozygous for the Esr1 knockout allele were also given intrauterine LPS to compare delivery and offspring viability to wild type controls. RESULTS The upregulation in inflammatory cytokines was accompanied by an increase in Esr1 and Esr2 transcripts, though protein levels declined. Cyp19 did not differ by mRNA or protein abundance. Offspring from Esr1 mutants were larger, had a longer gestation and significantly greater mortality. CONCLUSIONS Estrogen signaling is altered in the fetal brains of preterm offspring exposed to neuroinflammatory injury. The reduction of Esr1 and Esr2 proteins with LPS suggests that these proteins are degraded. It is possible that transcriptional upregulation of Esr1 and Esr2 occurs to compensate for the loss of these proteins. Alternatively, the translation of Esr1 and Esr2 mRNAs may be disrupted with LPS while a feedback mechanism upregulates transcription. Intact Esr1 signaling is also associated with early preterm delivery following exposure to intrauterine LPS. A loss of one Esr1 allele delays this process, but appears to do so at the cost of fetal viability. These results suggest estrogen signaling plays opposing roles between maternal and fetal responses to preterm birth.
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Affiliation(s)
- Stacey S Schmiedecke
- Division of Maternal Fetal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Andrew S Thagard
- Division of Maternal Fetal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Sarah M Edwards
- Division of Maternal Fetal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Rebecca L Talley
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Elisabeth M Dornisch
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Jennifer R Damicis
- Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington, USA
| | - Michael McLane
- Integrated Research Center for Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Irina Burd
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Peter G Napolitano
- Department of Obstetrics & Gynecology, University of Washington Medical Center, Seattle, Washington, USA
| | - Nicholas Ieronimakis
- Division of Maternal Fetal Medicine, Madigan Army Medical Center, Tacoma, Washington, USA.,Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington, USA
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22
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Rosenzweig R, Kumar V, Gupta S, Bermeo-Blanco O, Stratton MS, Gumina RJ, Bansal SS. Estrogen Receptor-β Agonists Modulate T-Lymphocyte Activation and Ameliorate Left Ventricular Remodeling During Chronic Heart Failure. Circ Heart Fail 2022; 15:e008997. [PMID: 35730443 DOI: 10.1161/circheartfailure.121.008997] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND CD4+ T cells temporally transition from protective to pathological during ischemic heart failure (HF; 8 weeks postmyocardial infarction). Cellular mechanisms mediating this shift are unknown. METHODS RNA-sequencing of cardiac CD4+ T cells and flow cytometric analysis of immune cells was conducted. RESULTS RNA-sequencing of CD4+ T cells from the failing hearts of male mice indicated activation of ER (estrogen receptor)-α signaling. Flow cytometric analysis showed that ERα in CD4+ T cells decreases significantly at 3-day postmyocardial infarction but increases during HF. To antagonize ERα, we tested a novel ERβ agonist (OSU-ERb-012) to inhibit T cells and blunt left ventricular remodeling. Proliferation assays showed that OSU-ERb-012 dose-dependently inhibited proliferation and proinflammatory cytokine expression in anti-CD3/CD28 stimulated splenic T cells isolated from both the sexes. For in vivo efficacy, 10- to 12-week-old male and ovariectomized female mice were randomized at 4 weeks postmyocardial infarction and treated with either vehicle or drug (60 mg/kg per day; oral). While vehicle-treated HF mice displayed progressive left ventricular dilatation with significantly increased end-systolic and end-diastolic volumes from 4 to 8 weeks postmyocardial infarction, treatment with OSU-ERb-012 significantly blunted these changes and stopped left ventricular remodeling in both the sexes. Reduction in tibia-normalized heart and left ventricular weights, cardiomyocyte hypertrophy and interstitial fibrosis further supported these results. Additionally, OSU-ERb-012 treatment selectively inhibited cardiac, splenic, and circulating CD4+ T cells without affecting other myeloid and lymphoid cells in the HF mice. CONCLUSIONS Our studies indicate that ERβ agonists and OSU-ERb-012, in particular, could be used as selective immunomodulatory drugs to inhibit CD4+ T cells during chronic HF.
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Affiliation(s)
- Rachel Rosenzweig
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.)
| | - Vinay Kumar
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.)
| | - Sahil Gupta
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.)
| | - Oscar Bermeo-Blanco
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.)
| | - Matthew S Stratton
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.)
| | - Richard J Gumina
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. (R.J.G., S.S.B.)
| | - Shyam S Bansal
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus. (R.R., V.K., S.G., O.B.-B., M.S.S., R.J.G., S.S.B.).,Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus. (R.J.G., S.S.B.)
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23
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Tsai HW, Lin VY, Shupnik MA. Forskolin Stimulates Estrogen Receptor (ER) α Transcriptional Activity and Protects ER from Degradation by Distinct Mechanisms. Int J Endocrinol 2022; 2022:7690166. [PMID: 35586275 PMCID: PMC9110234 DOI: 10.1155/2022/7690166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/01/2022] [Accepted: 03/15/2022] [Indexed: 11/30/2022] Open
Abstract
Estradiol action is mediated by estrogen receptors (ERs), a and ß. Estradiol binding initiates ER-mediated transcription and ER degradation, the latter of which occurs via the ubiquitin-proteasome pathway. Inhibition of proteasome activity prevents estradiol-induced ERα degradation and transactivation. In ER-positive GH3 cells (a rat pituitary prolactinoma cell line), forskolin, acting via protein kinase A (PKA), stimulates ERα transcriptional activity without causing degradation, and proteasome inhibition does not block forskolin-stimulated transcription. Forskolin also protects liganded ERα from degradation. In the current study, we first examined ERα and ERβ transcriptional activity in ER-negative HT22 cells and found that forskolin stimulated ERα-, but not ERβ-dependent transcription, through the ligand-binding domain (LBD). We also identified four mutations (L396R, D431Y, Y542F, and K534E/M548V) on the ERα LBD that selectively obliterated the response to forskolin. In GH3 cells, transfected ERα mutants and ERβ were protected from degradation by forskolin. Ubiquitination of ERα and ERβ was increased by forskolin or estradiol. ERα ubiquitination was diminished by a mutated ubiquitin (K48R) that prevents elongation of polyubiquitin chains for targeting the proteasome. Increased ERα ubiquitination was not affected by the deletion of the A/B domain but significantly diminished in the F domain deletion mutant. Our results indicate distinct and novel mechanisms for forskolin stimulation of ERα transcriptional activity and protection from ligand-induced degradation. It also suggests a unique mechanism by which forskolin increases unliganded and liganded ERα and ERβ ubiquitination but uncouples them from proteasome-mediated degradation regardless of their transcriptional responses to forskolin.
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Affiliation(s)
- Houng-Wei Tsai
- Department of Biological Sciences, California State University, Long Beach, CA 90840, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Vicky Y. Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Margaret A. Shupnik
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
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24
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Mohammadi Ghahhari N, Sznurkowska MK, Hulo N, Bernasconi L, Aceto N, Picard D. Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis. Nat Commun 2022; 13:2104. [PMID: 35440541 PMCID: PMC9018728 DOI: 10.1038/s41467-022-29723-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 03/30/2022] [Indexed: 02/08/2023] Open
Abstract
The epithelial to mesenchymal transition (EMT) has been proposed to contribute to the metastatic spread of breast cancer cells. EMT-promoting transcription factors determine a continuum of different EMT states. In contrast, estrogen receptor α (ERα) helps to maintain the epithelial phenotype of breast cancer cells and its expression is crucial for effective endocrine therapies. Determining whether and how EMT-associated transcription factors such as ZEB1 modulate ERα signaling during early stages of EMT could promote the discovery of therapeutic approaches to suppress metastasis. Here we show that, shortly after induction of EMT and while cells are still epithelial, ZEB1 modulates ERα-mediated transcription induced by estrogen or cAMP signaling in breast cancer cells. Based on these findings and our ex vivo and xenograft results, we suggest that the functional interaction between ZEB1 and ERα may alter the tissue tropism of metastatic breast cancer cells towards bone. The epithelial mesenchymal transition (EMT) is important in the metastatic spread of cancer cells. Here, the authors show that the EMT transcription factor, ZEB1, can modify estrogen receptor α during EMT and facilitate the migration of breast cancer cells to the bone
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Affiliation(s)
| | - Magdalena K Sznurkowska
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093, Zürich, Switzerland
| | - Nicolas Hulo
- Institute of Genetics and Genomics of Geneva, Université de Genève, 1211, Genève 4, Switzerland
| | - Lilia Bernasconi
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093, Zürich, Switzerland
| | - Didier Picard
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 1211, Genève 4, Switzerland.
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25
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Sun Y, Sangam S, Guo Q, Wang J, Tang H, Black SM, Desai AA. Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension. Front Cardiovasc Med 2021; 8:719058. [PMID: 34568460 PMCID: PMC8460911 DOI: 10.3389/fcvm.2021.719058] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/11/2021] [Indexed: 01/08/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the "estrogen paradox." Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.
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Affiliation(s)
- Yanan Sun
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shreya Sangam
- Department of Medicine, Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, United States
| | - Qiang Guo
- Department of Critical Care Medicine, Suzhou Dushu Lake Hospital, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Haiyang Tang
- College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Stephen M. Black
- Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Miami, FL, United States
- Center for Translational Science and Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Port St. Lucie, FL, United States
| | - Ankit A. Desai
- Department of Medicine, Krannert Institute of Cardiology, Indiana University, Indianapolis, IN, United States
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26
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Zamir-Nasta T, Pazhouhi M, Ghanbari A, Abdolmaleki A, Jalili C. Expression of cyclin D1, p21, and estrogen receptor alpha in aflatoxin G1-induced disturbance in testicular tissue of albino mice. Res Pharm Sci 2021; 16:182-192. [PMID: 34084205 PMCID: PMC8102931 DOI: 10.4103/1735-5362.310525] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/04/2020] [Accepted: 02/21/2021] [Indexed: 11/04/2022] Open
Abstract
Background and purpose Aflatoxin (AF) is a mycotoxin produced by various strains of the Aspergillus family. AFG1 as one of the most important types is highly found in cereals and grains. AF affects sperm production or even its quality. This study was designed to test the effects of AFG1 on mice testicular tissue. Experimental approach Twenty-four Albino mice were divided into four groups of 6 each; a control group (0.2 mL corn oil and ethanol), three treatment groups with different periods (20 μg/kg AFG1 for 7, 15, and 35 consecutive days). All treatments were applied intraperitoneally. Biosynthesis of cyclin D1, p21, and estrogen receptor alpha (ERα) proteins was evaluated by immunohistochemistry (IHC) staining. Levels of cyclin D1, p21, and ERα mRNA were evaluated by the real-time polymerase chain reaction (RT-PCR) technique. Tubular differentiation index (TDI), reproductive index (RI), and spermiogenesis indices were also analyzed. Findings/Results AFG1 increased the percentage of seminiferous tubules with negative TDI, RI, and SPI compared to the control group (P < 0.05). RT-PCR and IHC analyses illustrated time-dependent enhancement in p21 expression and cyclin D1 biosynthesis in AFG1-treated groups significantly (P < 0.05). While the protein and mRNA levels of ERα were significantly (P < 0.05) decreased in a time-dependent manner. Conclusion and implications The chronic exposure to AFG1 reduced the expression and synthesis of ERα, increased the expression and synthesis of p21 and cyclin D1, impaired apoptosis, which in turn could impair spermatogenesis.
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Affiliation(s)
- Toraj Zamir-Nasta
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Mona Pazhouhi
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Ali Ghanbari
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Amir Abdolmaleki
- Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
| | - Cyrus Jalili
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran
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27
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Farcas AM, Nagarajan S, Cosulich S, Carroll JS. Genome-Wide Estrogen Receptor Activity in Breast Cancer. Endocrinology 2021; 162:bqaa224. [PMID: 33284960 PMCID: PMC7787425 DOI: 10.1210/endocr/bqaa224] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Indexed: 12/13/2022]
Abstract
The largest subtype of breast cancer is characterized by the expression and activity of the estrogen receptor alpha (ERalpha/ER). Although several effective therapies have significantly improved survival, the adaptability of cancer cells means that patients frequently stop responding or develop resistance to endocrine treatment. ER does not function in isolation and multiple associating factors have been reported to play a role in regulating the estrogen-driven transcriptional program. This review focuses on the dynamic interplay between some of these factors which co-occupy ER-bound regulatory elements, their contribution to estrogen signaling, and their possible therapeutic applications. Furthermore, the review illustrates how some ER association partners can influence and reprogram the genomic distribution of the estrogen receptor. As this dynamic ER activity enables cancer cell adaptability and impacts the clinical outcome, defining how this plasticity is determined is fundamental to our understanding of the mechanisms of disease progression.
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Affiliation(s)
- Anca M Farcas
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Sankari Nagarajan
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | | | - Jason S Carroll
- CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
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28
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Suresh S, Huard S, Dubois T. CARM1/PRMT4: Making Its Mark beyond Its Function as a Transcriptional Coactivator. Trends Cell Biol 2021; 31:402-417. [PMID: 33485722 DOI: 10.1016/j.tcb.2020.12.010] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/16/2022]
Abstract
Coactivator-associated arginine methyltransferase 1 (CARM1), identified 20 years ago as a coregulator of transcription, is an enzyme that catalyzes arginine methylation of proteins. Beyond its well-established involvement in the regulation of transcription, the physiological functions of CARM1 are still poorly understood. However, recent studies have revealed novel roles of CARM1 in autophagy, metabolism, paraspeckles, and early development. In addition, CARM1 is emerging as an attractive therapeutic target and a drug response biomarker for certain types of cancer. Here, we provide a comprehensive overview of the structure of CARM1 and its post-translational modifications, its various functions, apart from transcriptional coactivation, and its involvement in cancer.
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Affiliation(s)
- Samyuktha Suresh
- Institut Curie - PSL Research University, Translational Research Department, Breast Cancer Biology Group, 75005 Paris, France
| | - Solène Huard
- Institut Curie - PSL Research University, Translational Research Department, Breast Cancer Biology Group, 75005 Paris, France
| | - Thierry Dubois
- Institut Curie - PSL Research University, Translational Research Department, Breast Cancer Biology Group, 75005 Paris, France.
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29
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Hermawan A, Putri H, Ikawati M. Bioinformatic analysis reveals the molecular targets of tangeretin in overcoming the resistance of breast cancer to tamoxifen. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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30
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Xiao Y, Kim M, Lazar MA. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Mol Metab 2020; 50:101119. [PMID: 33220489 PMCID: PMC8324695 DOI: 10.1016/j.molmet.2020.101119] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/13/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND As a result of a sedentary lifestyle and excess food consumption in modern society, non-alcoholic fatty liver disease (NAFLD) characterized by fat accumulation in the liver is becoming a major disease burden. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by inflammation and fibrosis that can lead to hepatocellular carcinoma and liver failure. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that closely control multiple aspects of metabolism. Their transcriptional activity is modulated by various ligands, including hormones and lipids. NRs serve as potential pharmacological targets for NAFLD/NASH and other metabolic diseases. SCOPE OF REVIEW In this review, we provide a comprehensive overview of NRs that have been studied in the context of NAFLD/NASH with a focus on their transcriptional regulation, function in preclinical models, and studies of their clinical utility. MAJOR CONCLUSIONS The transcriptional regulation of NRs is context-dependent. During the dynamic progression of NAFLD/NASH, NRs play diverse roles in multiple organs and different cell types in the liver, which highlights the necessity of targeting NRs in a stage-specific and cell-type-specific manner to enhance the efficacy and safety of treatment methods.
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Affiliation(s)
- Yang Xiao
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mindy Kim
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
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31
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Stewart MK, Mattiske DM, Pask AJ. Exogenous Oestrogen Impacts Cell Fate Decision in the Developing Gonads: A Potential Cause of Declining Human Reproductive Health. Int J Mol Sci 2020; 21:E8377. [PMID: 33171657 PMCID: PMC7664701 DOI: 10.3390/ijms21218377] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/06/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
The increasing incidence of testicular dysgenesis syndrome-related conditions and overall decline in human fertility has been linked to the prevalence of oestrogenic endocrine disrupting chemicals (EDCs) in the environment. Ectopic activation of oestrogen signalling by EDCs in the gonad can impact testis and ovary function and development. Oestrogen is the critical driver of ovarian differentiation in non-mammalian vertebrates, and in its absence a testis will form. In contrast, oestrogen is not required for mammalian ovarian differentiation, but it is essential for its maintenance, illustrating it is necessary for reinforcing ovarian fate. Interestingly, exposure of the bi-potential gonad to exogenous oestrogen can cause XY sex reversal in marsupials and this is mediated by the cytoplasmic retention of the testis-determining factor SOX9 (sex-determining region Y box transcription factor 9). Oestrogen can similarly suppress SOX9 and activate ovarian genes in both humans and mice, demonstrating it plays an essential role in all mammals in mediating gonad somatic cell fate. Here, we review the molecular control of gonad differentiation and explore the mechanisms through which exogenous oestrogen can influence somatic cell fate to disrupt gonad development and function. Understanding these mechanisms is essential for defining the effects of oestrogenic EDCs on the developing gonads and ultimately their impacts on human reproductive health.
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Affiliation(s)
- Melanie K. Stewart
- School of BioSciences, The University of Melbourne, Melbourne, VIC 3010, Australia; (D.M.M.); (A.J.P.)
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Song XQ, Liu RP, Wang SQ, Li Z, Ma ZY, Zhang R, Xie CZ, Qiao X, Xu JY. Anticancer Melatplatin Prodrugs: High Effect and Low Toxicity, MT1-ER-Target and Immune Response In Vivo. J Med Chem 2020; 63:6096-6106. [PMID: 32401032 DOI: 10.1021/acs.jmedchem.0c00343] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multitargeted therapy could rectify various oncogenic pathways to block tumorigenesis and progression. The combination of endocrine-, immune-, and chemotherapy might exert a highly synergistic effect against certain tumors. Herein, a series of smart Pt(IV) prodrugs 3-6, named Melatplatin, were rationally designed not only to multitarget DNA, MT1, and estrogen receptor (ER) but also to activate immune response. Melatplatin, conjugating first-line chemotherapeutic Pt drugs with human endogenous melatonin (MT), significantly enhanced drug efficacy especially in ER high-expression (ER+) cells, among which 3 presented the most potent cytotoxicity toward ER+ MCF-7 with nanomolar IC50 values 100-fold lower than cisplatin. Melatplatin could bind well to melatonin receptor (MT1) according to molecular docking. Besides, 3 evidently increased intracellular accumulation and DNA damage, upregulated γH2AX and P53, and silenced NF-κB to induce massive apoptosis. Most strikingly, 3 effectively inhibited tumor growth and attenuated systemic toxicity compared to cisplatin in vivo, promoting lymphocyte proliferation in spleen to achieve immune modulation.
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Affiliation(s)
- Xue-Qing Song
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Rui-Ping Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Shu-Qing Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Zhe Li
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Zhong-Ying Ma
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Ran Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Cheng-Zhi Xie
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Xin Qiao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Jing-Yuan Xu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
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Liu J, Feng J, Li L, Lin L, Ji J, Lin C, Liu L, Zhang N, Duan D, Li Z, Huang B, Zhang Y, Lu J. Arginine methylation-dependent LSD1 stability promotes invasion and metastasis of breast cancer. EMBO Rep 2020; 21:e48597. [PMID: 31833203 PMCID: PMC7001506 DOI: 10.15252/embr.201948597] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 11/11/2019] [Accepted: 11/18/2019] [Indexed: 12/22/2022] Open
Abstract
Histone lysine demethylase 1 (LSD1), the first identified histone demethylase, is overexpressed in multiple tumor types, including breast cancer. However, the mechanisms that cause LSD1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 4 (PRMT4 or CARM1) dimethylates LSD1 at R838, which promotes the binding of the deubiquitinase USP7, resulting in the deubiquitination and stabilization of LSD1. Moreover, CARM1- and USP7-dependent LSD1 stabilization plays a key role in repressing E-cadherin and activating vimentin transcription through promoter H3K4me2 and H3K9me2 demethylation, respectively, which promotes invasion and metastasis of breast cancer cells. Consistently, LSD1 arginine methylation levels correlate with tumor grade in human malignant breast carcinoma samples. Our findings unveil a unique mechanism controlling LSD1 stability by arginine methylation, also highlighting the role of the CARM1-USP7-LSD1 axis in breast cancer progression.
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Affiliation(s)
- Jiwei Liu
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jingxin Feng
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
- Present address:
Laboratory of Cellular OncologyCenter for Cancer Research (CCR)National Cancer Institute (NCI)BethesdaMDUSA
| | - Lili Li
- Key Laboratory of Cancer Prevention and TherapyDepartment of Bone and Soft Tissue OncologyNational Clinical Research Center for CancerTianjin Medical University Cancer Institute and HospitalTianjinChina
| | - Luyao Lin
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jiafei Ji
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Cong Lin
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Lingxia Liu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Na Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Dandan Duan
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Zhongwei Li
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Baiqu Huang
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
| | - Yu Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE)Northeast Normal UniversityChangchunChina
| | - Jun Lu
- The Institute of Genetics and CytologyNortheast Normal UniversityChangchunChina
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Jarrold J, Davies CC. PRMTs and Arginine Methylation: Cancer's Best-Kept Secret? Trends Mol Med 2019; 25:993-1009. [PMID: 31230909 DOI: 10.1016/j.molmed.2019.05.007] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 05/10/2019] [Accepted: 05/16/2019] [Indexed: 12/19/2022]
Abstract
Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy.
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Affiliation(s)
- James Jarrold
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Clare C Davies
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
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Rakow S, Pullamsetti SS, Bauer UM, Bouchard C. Assaying epigenome functions of PRMTs and their substrates. Methods 2019; 175:53-65. [PMID: 31542509 DOI: 10.1016/j.ymeth.2019.09.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 09/09/2019] [Accepted: 09/16/2019] [Indexed: 12/20/2022] Open
Abstract
Among the widespread and increasing number of identified post-translational modifications (PTMs), arginine methylation is catalyzed by the protein arginine methyltransferases (PRMTs) and regulates fundamental processes in cells, such as gene regulation, RNA processing, translation, and signal transduction. As epigenetic regulators, PRMTs play key roles in pluripotency, differentiation, proliferation, survival, and apoptosis, which are essential biological programs leading to development, adult homeostasis but also pathological conditions including cancer. A full understanding of the molecular mechanisms that underlie PRMT-mediated gene regulation requires the genome wide mapping of each player, i.e., PRMTs, their substrates and epigenetic marks, methyl-marks readers as well as interaction partners, in a thorough and unambiguous manner. However, despite the tremendous advances in high throughput sequencing technologies and the numerous efforts from the scientific community, the epigenomic profiling of PRMTs as well as their histone and non-histone substrates still remains a big challenge owing to obvious limitations in tools and methodologies. This review will summarize the present knowledge about the genome wide mapping of PRMTs and their substrates as well as the technical approaches currently in use. The limitations and pitfalls of the technical tools along with conventional approaches will be then discussed in detail. Finally, potential new strategies for chromatin profiling of PRMTs and histone substrates will be proposed and described.
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Affiliation(s)
- Sinja Rakow
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany
| | - Soni Savai Pullamsetti
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany
| | - Uta-Maria Bauer
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany
| | - Caroline Bouchard
- Institute for Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein-Str. 2, BMFZ, 35043 Marburg, Germany.
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Bao J, Rousseaux S, Shen J, Lin K, Lu Y, Bedford MT. The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis. Nucleic Acids Res 2019; 46:4327-4343. [PMID: 29659998 PMCID: PMC5961101 DOI: 10.1093/nar/gky240] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/26/2018] [Indexed: 01/04/2023] Open
Abstract
CARM1 is a protein arginine methyltransferase (PRMT) that has been firmly implicated in transcriptional regulation. However, the molecular mechanisms by which CARM1 orchestrates transcriptional regulation are not fully understood, especially in a tissue-specific context. We found that Carm1 is highly expressed in the mouse testis and localizes to the nucleus in spermatids, suggesting an important role for Carm1 in spermiogenesis. Using a germline-specific conditional Carm1 knockout mouse model, we found that it is essential for the late stages of haploid germ cell development. Loss of Carm1 led to a low sperm count and deformed sperm heads that can be attributed to defective elongation of round spermatids. RNA-seq analysis of Carm1-null spermatids revealed that the deregulated genes fell into similar categories as those impacted by p300-loss, thus providing a link between Carm1 and p300. Importantly, p300 has long been known to be a major Carm1 substrate. We found that CREMτ, a key testis-specific transcription factor, associates with p300 through its activator, ACT, and that this interaction is negatively regulated by the methylation of p300 by Carm1. Thus, high nuclear Carm1 levels negatively impact the p300•ACT•CREMτ axis during late stages of spermiogenesis.
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Affiliation(s)
- Jianqiang Bao
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Sophie Rousseaux
- CNRS UMR 5309, INSERM U1209, Université Grenoble Alpes, Institute for Advanced Biosciences, La Tronche, France
| | - Jianjun Shen
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA
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Wang SCM, Dowhan DH, Muscat GEO. Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies. J Mol Endocrinol 2019; 62:R223-R237. [PMID: 30620710 DOI: 10.1530/jme-18-0224] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 01/07/2019] [Indexed: 02/06/2023]
Abstract
Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.
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Affiliation(s)
- Shu-Ching M Wang
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
| | - Dennis H Dowhan
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
| | - George E O Muscat
- Cell Biology and Molecular Medicine Division, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Australia
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38
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Cheng D, Vemulapalli V, Lu Y, Shen J, Aoyagi S, Fry CJ, Yang Y, Foulds CE, Stossi F, Treviño LS, Mancini MA, O'Malley BW, Walker CL, Boyer TG, Bedford MT. CARM1 methylates MED12 to regulate its RNA-binding ability. Life Sci Alliance 2018; 1:e201800117. [PMID: 30456381 PMCID: PMC6238599 DOI: 10.26508/lsa.201800117] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/06/2018] [Accepted: 09/07/2018] [Indexed: 01/21/2023] Open
Abstract
CARM1 methylates MED12 at arginine 1899 to generate a TDRD3 binding site, which in turn regulates the ability of mediator to interact with activating ncRNAs and modulate gene expression. The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R1899), which interacts with the Tudor domain–containing effector molecule, TDRD3. Chromatin immunoprecipitation–seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERα-specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R1899 site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs.
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Affiliation(s)
- Donghang Cheng
- Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA
| | - Vidyasiri Vemulapalli
- Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA
| | - Jianjun Shen
- Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA
| | | | | | - Yanzhong Yang
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute at City of Hope, Duarte, CA, USA
| | - Charles E Foulds
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
| | - Fabio Stossi
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Lindsey S Treviño
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
| | - Michael A Mancini
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Bert W O'Malley
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Cheryl L Walker
- Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA
| | - Thomas G Boyer
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Mark T Bedford
- Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA
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Berto M, Jean V, Zwart W, Picard D. ERα activity depends on interaction and target site corecruitment with phosphorylated CREB1. Life Sci Alliance 2018; 1:e201800055. [PMID: 30456355 PMCID: PMC6238530 DOI: 10.26508/lsa.201800055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/18/2018] [Accepted: 05/22/2018] [Indexed: 12/17/2022] Open
Abstract
The two transcription factors estrogen receptor α (ERα) and cyclic adenosine monophosphate (cAMP)-responsive element binding protein 1 (CREB1) mediate different signals, bind different response elements, and control different transcriptional programs. And yet, results obtained with transfected reporter genes suggested that their activities may intersect. We demonstrate here that CREB1 stimulates and is necessary for ERα activity on a transfected reporter gene and several endogenous targets both in response to its cognate ligand estrogen and to ligand-independent activation by cAMP. The stimulatory activity of CREB1 requires its DNA binding and activation by phosphorylation, and affects the chromatin recruitment of ERα. CREB1 and ERα are biochemically associated and share hundreds to thousands of chromatin binding sites upon stimulation by estrogen and cAMP, respectively. These shared regulatory activities may underlie the anti-apoptotic effects of estrogen and cAMP signaling in ERα-positive breast cancer cells. Moreover, high levels of CREB1 are associated with good prognosis in ERα-positive breast cancer patients, which may be because of its ability to promote ERα functions, thereby maintaining it as a successful therapeutic target.
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Affiliation(s)
- Melissa Berto
- Département de Biologie Cellulaire and Institute of Genetics and Genomics of Geneva, Université de Genève, Genève, Switzerland
| | - Valerie Jean
- Département de Biologie Cellulaire and Institute of Genetics and Genomics of Geneva, Université de Genève, Genève, Switzerland
| | - Wilbert Zwart
- Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Didier Picard
- Département de Biologie Cellulaire and Institute of Genetics and Genomics of Geneva, Université de Genève, Genève, Switzerland
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Zamir-Nasta T, Razi M, Shapour H, Malekinejad H. Roles of p21, p53, cyclin D1, CDK-4, estrogen receptor α in aflatoxin B1-induced cytotoxicity in testicular tissue of mice. ENVIRONMENTAL TOXICOLOGY 2018; 33:385-395. [PMID: 29274131 DOI: 10.1002/tox.22524] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 11/20/2017] [Accepted: 12/02/2017] [Indexed: 06/07/2023]
Abstract
This study was done in order to investigate time-dependent effect of AFB1 on expression of genes involving in cell cycle check point machinery at G, S, and M phases. For this purpose, 24 mature male Swiss albino mice were randomly divided into control and test groups. The animals in test group subdivided into three groups, which received the AFB1 at a daily dose of 20 µg/kg body weight, through intraperitoneal (i.p.) route, for 7, 14, and 21 days. The p21, p53, cyclin D1, CDK4, and ERα expressions at both mRNA and protein level were analyzed by using reverse transcription PCR (RT-PCR) and immunohistochemistry, respectively. Moreover, the tubular differentiation (TDI) and spermiogenesis (SPI) indices were analyzed. Finally, the testicular DNA fragmentation was assessed by using DNA Ladder test. Observations revealed that the AFB1 remarkably (P < .05) reduced cyclin D1, Cdk4, and ERα expression at both mRNA and protein levels. Up-regulated p21 and p53 expression was revealed in AFB1-received animals, which developed time dependently. Histological examinations exhibited a significant reduction in TDI and SPI indices. Finally, the AFB1 resulted in severe DNA fragmentation. Our data showed that the AFB1 by down-regulating the cyclin D1, Cdk4, and ERα expression adversely affects cyclin D1/Cdk4 and cyclin D1/ERα interactions. Moreover, the AFB1-induced overexpression of p21 (as a kinase inhibitor), in turn results in cell cycle arrest via inhibiting the Cdk4 interaction with cyclin D1. Finally, the AFB1-induced DNA damage triggers the p53-dependent apoptosis pathway independent to p21 overexpression.
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Affiliation(s)
- Toraj Zamir-Nasta
- Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, P.O. Box 1177, Urmia, Iran
| | - Mazdak Razi
- Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, P.O. Box 1177, Urmia, Iran
| | - Hasanzadeh Shapour
- Department of Basic Science, Faculty of Veterinary Medicine, Urmia University, P.O. Box 1177, Urmia, Iran
| | - Hassan Malekinejad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
- Food and Beverages Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran
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Wang Z, Kanda S, Shimono T, Enkh-Undraa D, Nishiyama T. The in vitro estrogenic activity of the crude drugs found in Japanese herbal medicines prescribed for menopausal syndrome was enhanced by combining them. Altern Ther Health Med 2018; 18:107. [PMID: 29566679 PMCID: PMC5865359 DOI: 10.1186/s12906-018-2170-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 03/15/2018] [Indexed: 01/28/2023]
Abstract
BACKGROUND Japanese herbal medicines can be used as alternatives to estrogen therapy and are sometimes prescribed for menopausal syndrome because they have fewer side effects and are associated with better compliance than estrogen therapy, but little is known about the pharmacological mechanisms of such treatments. This study aimed to explore the mechanisms responsible for the estrogen-like effects of five widely prescribed Japanese herbal medicines (unkeito, kamishoyosan, nyoshinsan, keishibukuryogan, and tokishakuyakusan). METHODS We evaluated the estrogenic activity of these five Japanese herbal medicines and their metabolites using an estrogen receptor (ER)-dependent cell proliferation bioassay and an ER-dependent reporter assay. We also investigated the estrogenic activity of the crude drugs within the medicines and attempted to detect inter-crude drug synergistic effects using the ER-dependent reporter assay. RESULTS We found that unkeito, kamishoyosan, and nyoshinsan exhibited estrogenic activity, and they displayed stronger estrogenic activity after being metabolized. Then, we focused on investigating the estrogenic activity of the crude drugs present within unkeito. We found that glycyrrhizae radix, cinnamomi cortex, evodiae fructus, and zingiberis rhizoma demonstrated ERβ-dependent estrogenic activity. The combined use of evodiae fructus and glycyrrhizae radix, or evodiae fructus and cinnamomi cortex produced synergistic ERβ-dependent estrogenic activity. CONCLUSION It was suggested that unkeito, kamishoyosan, and nyoshinsan exert estrogenic activity, and hence, might be useful for treating menopausal syndrome. Furthermore, synergistic estrogenic effects were detected between some of the crude drugs present within unkeito.
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Park J, Lee Y. Hypoxia induced phosphorylation of estrogen receptor at serine 118 in the absence of ligand. J Steroid Biochem Mol Biol 2017; 174:146-152. [PMID: 28847747 DOI: 10.1016/j.jsbmb.2017.08.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 08/18/2017] [Accepted: 08/21/2017] [Indexed: 10/19/2022]
Abstract
The estrogen receptor (ER) plays an important role in breast cancer development and progression. Hypoxia modulates the level of ERα expression and induces ligand-independent transcriptional activation of ERα, which is closely related with the biology of breast carcinomas. Since phosphorylation itself affects the transcriptional activity and stabilization of ERα, we examined changes in ERα phosphorylation under hypoxic conditions. Hypoxia induced phosphorylation of ERα at serine residue 118 (S118) in the absence of estrogen through the mitogen-activated protein kinase (MAPK)/ERK1/2 pathway. Cell proliferation was significantly decreased under normoxia or hypoxia when ERα harboring the S118A mutation was overexpressed. Our previous studies showed that ER degradation is the most prominent phenomenon under hypoxia. E2-induced ER protein downregulation is dependent on phosphorylation of S118. However, hypoxia-induced ERα degradation did not involve S118 phosphorylation. Our study implies the existence of a differential mechanism between E2 and hypoxia-mediated ERα protein degradation. Understanding the mechanistic behavior of ER under hypoxia will likely facilitate understanding of endocrine therapy resistance and development of treatment strategies for breast cancer.
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Affiliation(s)
- Joonwoo Park
- College of Life Science, Department of Integrated Bioscience and Biotechnology, Sejong University, Seoul 143-747, South Korea
| | - YoungJoo Lee
- College of Life Science, Department of Integrated Bioscience and Biotechnology, Sejong University, Seoul 143-747, South Korea.
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43
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Ghosh S, Klein RS. Sex Drives Dimorphic Immune Responses to Viral Infections. THE JOURNAL OF IMMUNOLOGY 2017; 198:1782-1790. [PMID: 28223406 DOI: 10.4049/jimmunol.1601166] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 10/24/2016] [Indexed: 02/07/2023]
Abstract
New attention to sexual dimorphism in normal mammalian physiology and disease has uncovered a previously unappreciated breadth of mechanisms by which females and males differentially exhibit quantitative phenotypes. Thus, in addition to the established modifying effects of hormones, which prenatally and postpubertally pattern cells and tissues in a sexually dimorphic fashion, sex differences are caused by extragonadal and dosage effects of genes encoded on sex chromosomes. Sex differences in immune responses, especially during autoimmunity, have been studied predominantly within the context of sex hormone effects. More recently, immune response genes have been localized to sex chromosomes themselves or found to be regulated by sex chromosome genes. Thus, understanding how sex impacts immunity requires the elucidation of complex interactions among sex hormones, sex chromosomes, and immune response genes. In this Brief Review, we discuss current knowledge and new insights into these intricate relationships in the context of viral infections.
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Affiliation(s)
- Soumitra Ghosh
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Robyn S Klein
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110; .,Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and.,Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110
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Kuo LC, Cheng LC, Lee CH, Lin CJ, Chen PY, Li LA. Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells. Am J Physiol Lung Cell Mol Physiol 2017; 313:L477-L490. [DOI: 10.1152/ajplung.00322.2016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 05/11/2017] [Accepted: 05/11/2017] [Indexed: 01/23/2023] Open
Abstract
Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17β-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3β activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.
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Affiliation(s)
- Lun-Cheng Kuo
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan; and
| | - Li-Chuan Cheng
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan; and
| | - Chia-Huei Lee
- National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan
| | - Chun-Ju Lin
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan; and
| | - Pei-Yu Chen
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan; and
| | - Lih-Ann Li
- National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan; and
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Therapeutic Use of Estrogen Receptor β Agonists in Prevention and Treatment of Endocrine Therapy Resistant Breast Cancers: Observations From Preclinical Models. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 151:177-194. [DOI: 10.1016/bs.pmbts.2017.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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46
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Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer. Oncogene 2016; 36:2319-2327. [PMID: 27869171 PMCID: PMC5398938 DOI: 10.1038/onc.2016.397] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 09/07/2016] [Accepted: 09/08/2016] [Indexed: 12/19/2022]
Abstract
Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.
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Wang YP, Zhou W, Wang J, Huang X, Zuo Y, Wang TS, Gao X, Xu YY, Zou SW, Liu YB, Cheng JK, Lei QY. Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer. Mol Cell 2016; 64:673-687. [PMID: 27840030 DOI: 10.1016/j.molcel.2016.09.028] [Citation(s) in RCA: 152] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 08/24/2016] [Accepted: 09/21/2016] [Indexed: 12/28/2022]
Abstract
Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.
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Affiliation(s)
- Yi-Ping Wang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Wei Zhou
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jian Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xian Huang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yong Zuo
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Tian-Shi Wang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xue Gao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Ying-Ying Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Shao-Wu Zou
- Department of Hepatopancreatobiliary Surgery, Shanghai Tenth People's Hospital, Tong Ji University, Shanghai 200072, China
| | - Ying-Bin Liu
- Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Jin-Ke Cheng
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Qun-Ying Lei
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
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Bennesch MA, Segala G, Wider D, Picard D. LSD1 engages a corepressor complex for the activation of the estrogen receptor α by estrogen and cAMP. Nucleic Acids Res 2016; 44:8655-8670. [PMID: 27325688 PMCID: PMC5062963 DOI: 10.1093/nar/gkw522] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/28/2016] [Indexed: 02/06/2023] Open
Abstract
The estrogen receptor α (ERα) is a transcription factor that can be directly activated by estrogen or indirectly by other signaling pathways. We previously reported that activation of the unliganded ERα by cAMP is mediated by phosphorylation of the transcriptional coactivator CARM1 by protein kinase A (PKA), allowing CARM1 to bind ERα directly. This being insufficient by itself to activate ERα, we looked for additional factors and identified the histone H3 demethylase LSD1 as a substrate of PKA and an important mediator of this signaling crosstalk as well as of the response to estrogen. Surprisingly, ERα engages not only LSD1, but its partners of the CoREST corepressor complex and the molecular chaperone Hsp90. The recruitment of Hsp90 to promote ERα transcriptional activity runs against the steroid receptor paradigm and suggests that it might be involved as an assembly factor or scaffold. In a breast cancer cell line, which is resistant to the anti-estrogen tamoxifen because of constitutively activated PKA, some interactions are constitutive and drug combinations partially rescue tamoxifen sensitivity. In ERα-positive breast cancer patients, high expression of the genes encoding some of these factors correlates with poor prognosis. Thus, these mechanisms might contribute to ERα-driven breast cancer.
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Affiliation(s)
- Marcela A Bennesch
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, CH-1211 Genève 4, Switzerland
| | - Gregory Segala
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, CH-1211 Genève 4, Switzerland
| | - Diana Wider
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, CH-1211 Genève 4, Switzerland
| | - Didier Picard
- Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, CH-1211 Genève 4, Switzerland
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Lu KT, Keen HL, Weatherford ET, Sequeira-Lopez MLS, Gomez RA, Sigmund CD. Estrogen Receptor α Is Required for Maintaining Baseline Renin Expression. Hypertension 2016; 67:992-9. [PMID: 26928806 DOI: 10.1161/hypertensionaha.115.07082] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 02/08/2016] [Indexed: 01/08/2023]
Abstract
Enzymatic cleavage of angiotensinogen by renin represents the critical rate-limiting step in the production of angiotensin II, but the mechanisms regulating the initial expression of the renin gene remain incomplete. The purpose of this study is to unravel the molecular mechanism controlling renin expression. We identified a subset of nuclear receptors that exhibited an expression pattern similar to renin by reanalyzing a publicly available microarray data set. Expression of some of these nuclear receptors was similarly regulated as renin in response to physiological cues, which are known to regulate renin. Among these, only estrogen receptor α (ERα) and hepatic nuclear factor α have no known function in regulating renin expression. We determined that ERα is essential for the maintenance of renin expression by transfection of small interfering RNAs targeting Esr1, the gene encoding ERα, in renin-expressing As4.1 cells. We also observed that previously characterized negative regulators of renin expression, Nr2f2 and vitamin D receptor, exhibited elevated expression in response to ERα inhibition. Therefore, we tested whether ERα regulates renin expression through an interaction with Nr2f2 and vitamin D receptor. Renin expression did not return to baseline when we concurrently suppressed both Esr1 and Nr2f2 or Esr1 and vitamin D receptor mRNAs, strongly suggesting that Esr1 regulates renin expression independent of Nr2f2 and vitamin D receptor. ERα directly binds to the hormone response element within the renin enhancer region. We conclude that ERα is a previously unknown regulator of renin that directly binds to the renin enhancer hormone response element sequence and is critical in maintaining renin expression in renin-expressing As4.1 cells.
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Affiliation(s)
- Ko-Ting Lu
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.)
| | - Henry L Keen
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.)
| | - Eric T Weatherford
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.)
| | - Maria Luisa S Sequeira-Lopez
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.)
| | - R Ariel Gomez
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.)
| | - Curt D Sigmund
- From the Department of Pharmacology (K.-T.L., H.L.K., E.T.W., C.D.S.) and Center for Hypertension Research (C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Pediatrics, University of Virginia, Charlottesville (M.L.S.S.-L., R.A.G.).
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50
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de Anda-Jáuregui G, Mejía-Pedroza RA, Espinal-Enríquez J, Hernández-Lemus E. Crosstalk events in the estrogen signaling pathway may affect tamoxifen efficacy in breast cancer molecular subtypes. Comput Biol Chem 2015; 59 Pt B:42-54. [PMID: 26345254 DOI: 10.1016/j.compbiolchem.2015.07.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 07/02/2015] [Accepted: 07/10/2015] [Indexed: 12/15/2022]
Abstract
Steroid hormones are involved on cell growth, development and differentiation. Such effects are often mediated by steroid receptors. One paradigmatic example of this coupling is the estrogen signaling pathway. Its dysregulation is involved in most tumors of the mammary gland. It is thus an important pharmacological target in breast cancer. This pathway, however, crosstalks with several other molecular pathways, a fact that may have consequences for the effectiveness of hormone modulating drug therapies, such as tamoxifen. For this work, we performed a systematic analysis of the major routes involved in crosstalk phenomena with the estrogen pathway - based on gene expression experiments (819 samples) and pathway analysis (493 samples) - for biopsy-captured tissue and contrasted in two independent datasets with in vivo and in vitro pharmacological stimulation. Our results confirm the presence of a number of crosstalk events across the estrogen signaling pathway with others that are dysregulated in different molecular subtypes of breast cancer. These may be involved in proliferation, invasiveness and apoptosis-evasion in patients. The results presented may open the way to new designs of adjuvant and neoadjuvant therapies for breast cancer treatment.
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Affiliation(s)
| | - Raúl A Mejía-Pedroza
- Computational Genomics Department, National Institute of Genomic Medicine (INMEGEN), Mexico
| | - Jesús Espinal-Enríquez
- Computational Genomics Department, National Institute of Genomic Medicine (INMEGEN), Mexico; Center for Complexity Sciences, National Autonomous University of México (UNAM), Mexico
| | - Enrique Hernández-Lemus
- Computational Genomics Department, National Institute of Genomic Medicine (INMEGEN), Mexico; Center for Complexity Sciences, National Autonomous University of México (UNAM), Mexico.
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