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1
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Zhou J, Gou YK, Guo D, Wang MY, Liu P. Roles of gastric cancer-derived exosomes in the occurrence of metastatic hepatocellular carcinoma. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 196:1-7. [PMID: 39884558 DOI: 10.1016/j.pbiomolbio.2025.01.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/20/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Gastric cancer (GC), particularly in East Asia, is among the most prevalent cancers with high mortality rates. According to recent epidemiological data, patients with GC account for over a quarter of all cancer incidences and approximately one third of cancer-related deaths in East Asia. Liver metastasis (LM) is not only a common form of GC distant metastasis but also poses a major challenge to the prognosis and treatment of patients with advanced GC. Increasing evidence has shown that the gut-liver axis plays a pivotal role in maintaining the stomach-liver-gut homeostasis. Exosomes are small secreted vesicles enriched with specific proteins, lipids, and nucleic acids. These vesicles exhibit significant activities in signal transmission to adjacent or distant cells in the gut-liver axis, as well as in remodeling the tumor microenvironment. Some research have pointed out that exosomes promote LM of various cancers. However, there still lack of complete and systematic review on how exosomes affect GC-LM. In this article, we present a comprehensive description to explore the role of GC-derived exosomes in the occurrence and development of metastatic hepatocellular carcinoma (HCC).
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Affiliation(s)
- Jie Zhou
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, 261053, PR China; Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Yuan-Kun Gou
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, 261053, PR China; Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Dong Guo
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China
| | - Ming-Yi Wang
- School of Medical Laboratory, Shandong Second Medical University, Weifang, Shandong, 261053, PR China; Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China.
| | - Peng Liu
- Department of Central Lab, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, Shandong, 264200, PR China.
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2
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Angulo M, Ramos-Vega A, Angulo C. Trained immunity-based Adjuvated vaccines (TIbAV) approach: β-glucans as example. Vaccine 2025; 57:127240. [PMID: 40349457 DOI: 10.1016/j.vaccine.2025.127240] [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: 01/17/2025] [Revised: 04/23/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
The induction of trained immunity (TRIM) has emerged as an approach to fight against diseases. Several β-glucans and vaccines have been identified as trained immunity inductors, allowing heterologous protection for infectious diseases. Curiously, β-glucans from yeast, fungal, and plant species have been evaluated in clinical trials as vaccine adjuvants to combat infectious and non-communicable diseases. However, their adjuvant use for trained immunity-based vaccines (TIbV) remains scarcely studied. In this context, this review brings a scientific panorama of β-glucans and vaccines and offers perspectives on their combination to potentiate trained immunity induction and its benefits. In agreement with TRIM and TIbV concepts, we propose trained immunity-based adjuvanted vaccines (TIbAV) to refer to studies regarding this approach.
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Affiliation(s)
- Miriam Angulo
- Immunology & Vaccinology Group, Centro de Investigaciones Biológicas del Noroeste, S.C. Instituto Politécnico Nacional, 195, Playa Palo de Santa Rita Sur, La Paz, B.C.S. C.P. 23096, Mexico
| | - Abel Ramos-Vega
- Centro de Investigación en Ciencia Aplicada y Tecnología Avanzada (CICATA), Unidad Morelos del Instituto Politécnico Nacional (IPN). Dirección: Boulevard de la Tecnología No.1036, Código Postal 62790. Xochitepec, Morelos, Mexico
| | - Carlos Angulo
- Immunology & Vaccinology Group, Centro de Investigaciones Biológicas del Noroeste, S.C. Instituto Politécnico Nacional, 195, Playa Palo de Santa Rita Sur, La Paz, B.C.S. C.P. 23096, Mexico.
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3
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Dai C, Qianjiang H, Fu R, Yang H, Shi A, Luo H. Epigenetic and epitranscriptomic role of lncRNA in carcinogenesis (Review). Int J Oncol 2025; 66:29. [PMID: 40017127 PMCID: PMC11900940 DOI: 10.3892/ijo.2025.5735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Long non‑coding RNAs (lncRNAs) are key players in the regulation of gene expression by mediating epigenetic and epitranscriptomic modification. Dysregulation of lncRNAs is implicated in tumor initiation, progression and metastasis. lncRNAs modulate chromatin structure and gene transcription by recruiting epigenetic regulators, including DNA‑ or histone‑modifying enzymes. Additionally, lncRNAs mediate chromatin remodeling and enhancer‑promoter long‑range chromatin interactions to control oncogene expression by recruiting chromatin organization‑associated proteins, thereby promoting carcinogenesis. Furthermore, lncRNAs aberrantly induce oncogene expression by mediating epitranscriptomic modifications, including RNA methylation and RNA editing. The present study aimed to summarize the regulatory mechanisms of lncRNAs in cancer to unravel the complex interplay between lncRNAs and epigenetic/epitranscriptomic regulators in carcinogenesis. The present review aimed to provide a novel perspective on the epigenetic and epitranscriptomic roles of lncRNAs in carcinogenesis to facilitate identification of potential biomarkers and therapeutic targets for cancer diagnosis and treatment.
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Affiliation(s)
- Chunfei Dai
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
| | - Haoyue Qianjiang
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, P.R. China
| | - Ruishuang Fu
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Huimin Yang
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
| | - Aiqin Shi
- Xianghu Laboratory, Hangzhou, Zhejiang 311231, P.R. China
| | - Huacheng Luo
- Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine, The Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
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4
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Gaggi G, Hausman C, Cho S, Badalamenti BC, Trinh BQ, Di Ruscio A, Ummarino S. LncRNAs Ride the Storm of Epigenetic Marks. Genes (Basel) 2025; 16:313. [PMID: 40149464 PMCID: PMC11942515 DOI: 10.3390/genes16030313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/29/2025] Open
Abstract
Advancements in genome sequencing technologies have uncovered the multifaceted roles of long non-coding RNAs (lncRNAs) in human cells. Recent discoveries have identified lncRNAs as major players in gene regulatory pathways, highlighting their pivotal role in human cell growth and development. Their dysregulation is implicated in the onset of genetic disorders and age-related diseases, including cancer. Specifically, they have been found to orchestrate molecular mechanisms impacting epigenetics, including DNA methylation and hydroxymethylation, histone modifications, and chromatin remodeling, thereby significantly influencing gene expression. This review provides an overview of the current knowledge on lncRNA-mediated epigenetic regulation of gene expression, emphasizing the biomedical implications of lncRNAs in the development of different types of cancers and genetic diseases.
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Affiliation(s)
- Giulia Gaggi
- Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- UdA-TechLab, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Clinton Hausman
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; (C.H.); (S.C.); (B.C.B.)
- Beth Israel Deaconess Medical Center, Cancer Research Institute, Boston, MA 02215, USA
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Soomin Cho
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; (C.H.); (S.C.); (B.C.B.)
- Beth Israel Deaconess Medical Center, Cancer Research Institute, Boston, MA 02215, USA
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Brianna C. Badalamenti
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; (C.H.); (S.C.); (B.C.B.)
- Beth Israel Deaconess Medical Center, Cancer Research Institute, Boston, MA 02215, USA
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Bon Q. Trinh
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA;
- Molecular Genetics & Epigenetics Program, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22908, USA
| | - Annalisa Di Ruscio
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; (C.H.); (S.C.); (B.C.B.)
- Beth Israel Deaconess Medical Center, Cancer Research Institute, Boston, MA 02215, USA
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Simone Ummarino
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; (C.H.); (S.C.); (B.C.B.)
- Beth Israel Deaconess Medical Center, Cancer Research Institute, Boston, MA 02215, USA
- Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA
- Department of Biology, Tufts University, Medford, MA 02155, USA
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5
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Bagheri-Mohammadi S, Karamivandishi A, Mahdavi SA, Siahposht-Khachaki A. New sights on long non-coding RNAs in glioblastoma: A review of molecular mechanism. Heliyon 2024; 10:e39744. [PMID: 39553554 PMCID: PMC11564028 DOI: 10.1016/j.heliyon.2024.e39744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/19/2024] Open
Abstract
Glioma or glioblastoma (GBM) is one of the aggressive and fatal primary cerebral malignancies, with the highest mortality rate among all brain-related tumors. Also, glioma mainly progresses as a more invasive phenotype after primary treatment. Cumulative evidence suggested that dysregulation of noncoding RNAs (ncRNAs) such as long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) are associated with tumor initiation, progression, and drug resistance, through epigenetic modifications, transcriptional, and post-transcriptional processes in the cells. Many scientific investigations have revealed that LncRNAs play important roles in various biological procedures linked with the development and progression of GBM. In recent years, it has been shown that dysregulation of molecular mechanisms in many LncRNAs such as MIR22HG, HULC, AGAP2-AS1, MALAT1, PVT1, TTTY14, HOTAIRM1, PTAR, LPP-AS2, LINC00336, and TINCR are connected with the GBM. Therefore, this scientific review paper focused on the molecular mechanisms of these LncRNAs in the context of GBM.
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Affiliation(s)
- Saeid Bagheri-Mohammadi
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
- Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Arezoo Karamivandishi
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seif Ali Mahdavi
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ali Siahposht-Khachaki
- Immunogenetics Research Center, Department of Physiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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6
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Wang S, Bai Y, Ma J, Qiao L, Zhang M. Long non-coding RNAs: regulators of autophagy and potential biomarkers in therapy resistance and urological cancers. Front Pharmacol 2024; 15:1442227. [PMID: 39512820 PMCID: PMC11540796 DOI: 10.3389/fphar.2024.1442227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024] Open
Abstract
The non-coding RNAs (ncRNAs) comprise a large part of human genome that mainly do not code for proteins. Although ncRNAs were first believed to be non-functional, the more investigations highlighted tthe possibility of ncRNAs in controlling vital biological processes. The length of long non-coding RNAs (lncRNAs) exceeds 200 nucleotidesand can be present in nucleus and cytoplasm. LncRNAs do not translate to proteins and they have been implicated in the regulation of tumorigenesis. On the other hand, One way cells die is by a process called autophagy, which breaks down proteins and other components in the cytoplasm., while the aberrant activation of autophagy allegedly involved in the pathogenesis of diseases. The autophagy exerts anti-cancer activity in pre-cancerous lesions, while it has oncogenic function in advanced stages of cancers. The current overview focuses on the connection between lncRNAs and autophagy in urological cancers is discussed. Notably, one possible role for lncRNAs is as diagnostic and prognostic variablesin urological cancers. The proliferation, metastasis, apoptosis and therapy response in prostate, bladder and renal cancers are regulated by lncRNAs. The changes in autophagy levels can also influence the apoptosis, proliferation and therapy response in urological tumors. Since lncRNAs have modulatory functions, they can affect autophagy mechanism to determine progression of urological cancers.
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Affiliation(s)
- Shizong Wang
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong, China
- Shangdong Provincial Key Laboratory for Prevention and Treatment of Urological Diseases in Medicine and Health, Weifang, Shandong, China
| | - Yang Bai
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong, China
- Shangdong Provincial Key Laboratory for Prevention and Treatment of Urological Diseases in Medicine and Health, Weifang, Shandong, China
| | - Jie Ma
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong, China
- Shangdong Provincial Key Laboratory for Prevention and Treatment of Urological Diseases in Medicine and Health, Weifang, Shandong, China
| | - Liang Qiao
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong, China
- Shangdong Provincial Key Laboratory for Prevention and Treatment of Urological Diseases in Medicine and Health, Weifang, Shandong, China
| | - Mingqing Zhang
- Department of Urology, Weifang People’s Hospital, Weifang, Shandong, China
- Shangdong Provincial Key Laboratory for Prevention and Treatment of Urological Diseases in Medicine and Health, Weifang, Shandong, China
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7
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Maqbool M, Hussain MS, Bisht AS, Kumari A, Kamran A, Sultana A, Kumar R, Khan Y, Gupta G. Connecting the dots: LncRNAs in the KRAS pathway and cancer. Pathol Res Pract 2024; 262:155570. [PMID: 39226802 DOI: 10.1016/j.prp.2024.155570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/17/2024] [Accepted: 08/28/2024] [Indexed: 09/05/2024]
Abstract
Long non-coding RNAs (lncRNAs) have been identified as important participants in several biological functions, particularly their complex interactions with the KRAS pathway, which provide insights into the significant roles lncRNAs play in cancer development. The KRAS pathway, a central signaling cascade crucial for cell proliferation, survival, and differentiation, stands out as a key therapeutic target due to its aberrant activation in many human cancers. Recent investigations have unveiled a myriad of lncRNAs, such as H19, ANRIL, and MEG3, intricately modulating the KRAS pathway, influencing both its activation and repression through various mechanisms, including epigenetic modifications, transcriptional regulation, and post-transcriptional control. These lncRNAs function as fine-tuners, delicately orchestrating the balance required for normal cellular function. Their dysregulation has been linked to the development and progression of multiple malignancies, including lung, pancreatic, and colorectal carcinomas, which frequently harbor KRAS mutations. This scrutiny delves into the functional diversity of specific lncRNAs within the KRAS pathway, elucidating their molecular mechanisms and downstream effects on cancer phenotypes. Additionally, it underscores the diagnostic and prognostic potential of these lncRNAs as indicators for cancer detection and assessment. The complex regulatory network that lncRNAs construct within the context of the KRAS pathway offers important insights for the creation of focused therapeutic approaches, opening new possibilities for precision medicine in oncology. However, challenges such as the dual roles of lncRNAs in different cancer types and the difficulty in therapeutically targeting these molecules highlight the ongoing debates and need for further research. As ongoing studies unveil the complexities of lncRNA-mediated KRAS pathway modulation, the potential for innovative cancer interventions becomes increasingly promising.
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Affiliation(s)
- Mudasir Maqbool
- Department of Pharmaceutical Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Md Sadique Hussain
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, Uttarakhand 248007, India.
| | - Ajay Singh Bisht
- School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Patel Nagar, Dehradun, Uttarakhand 248001, India
| | - Alka Kumari
- University institute of pharmacy, Chandigarh University, Gharaun, Punjab 140413, India
| | - Almaz Kamran
- HIMT College of Pharmacy, Plot No. 08, Knowledge Park - 1, Greater Noida, Uttar Pradesh 201310, India
| | - Ayesha Sultana
- Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya University, Deralakatte, Mangalore, Karnataka, India
| | - Rajesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
| | - Yumna Khan
- Institute of Biotechnology and Genetic Engineering (Health Division), The University of Agriculture, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
| | - Gaurav Gupta
- Centre for Research Impact & Outcome-Chitkara College of Pharmacy, Chitkara University, Punjab, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
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8
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Chen W, Pan Z, Feng Z, Wang X, Zhu S. Deciphering the code: the pivotal role of lncRNAs in advancing TNBC therapy. Front Oncol 2024; 14:1450980. [PMID: 39286016 PMCID: PMC11402698 DOI: 10.3389/fonc.2024.1450980] [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: 06/18/2024] [Accepted: 08/05/2024] [Indexed: 09/19/2024] Open
Abstract
Triple-negative breast cancer (TNBC) represents the most formidable subtype of breast cancer, characterized by a notable dearth in targeted therapeutic options. Deciphering the underlying molecular mechanisms of TNBC is pivotal for improving patient outcomes. Recent scientific advancements have spotlighted long non-coding RNAs (lncRNAs) as key players in the genesis, progression, and metastasis of cancers. This review delineates the significant influence of lncRNAs on the advancement, detection, and neoadjuvant chemotherapy efficacy in TNBC, detailing the diverse expression patterns of aberrant lncRNAs. The paper explores the specific mechanisms by which lncRNAs regulate gene expression in both the nucleus and cytoplasm, with a special focus on their involvement in TNBC's post-transcriptional landscape. Thorough investigations into TNBC-associated lncRNAs not only forge new avenues for early diagnosis and potent treatment strategies but also highlight these molecules as promising therapeutic targets, heralding an era of personalized and precision medicine in TNBC management.
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Affiliation(s)
- Weiping Chen
- Department of Respiratory, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Zhiyong Pan
- Department of Radiotherapy, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Zhengfu Feng
- Department of Radiotherapy, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Xin Wang
- Department of Radiotherapy, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Song Zhu
- Department of Radiotherapy, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
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Aljabali AAA, Alkaraki AK, Gammoh O, Tambuwala MM, Mishra V, Mishra Y, Hassan SS, El-Tanani M. Deciphering Depression: Epigenetic Mechanisms and Treatment Strategies. BIOLOGY 2024; 13:638. [PMID: 39194576 PMCID: PMC11351889 DOI: 10.3390/biology13080638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/14/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies.
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Affiliation(s)
- Alaa A. A. Aljabali
- Faculty of Pharmacy, Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan
| | - Almuthanna K. Alkaraki
- Department of Biological Sciences, Faculty of Science, Yarmouk University, Irbid 21163, Jordan;
| | - Omar Gammoh
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan;
| | - Murtaza M. Tambuwala
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates; (M.M.T.); (M.E.-T.)
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Yachana Mishra
- School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Sk. Sarif Hassan
- Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram, Paschim Medinipur 721140, West Bengal, India;
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah P.O. Box 11172, United Arab Emirates; (M.M.T.); (M.E.-T.)
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10
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Sharma S, Houfani AA, Foster LJ. Pivotal functions and impact of long con-coding RNAs on cellular processes and genome integrity. J Biomed Sci 2024; 31:52. [PMID: 38745221 PMCID: PMC11092263 DOI: 10.1186/s12929-024-01038-1] [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: 10/24/2023] [Accepted: 04/30/2024] [Indexed: 05/16/2024] Open
Abstract
Recent advances in uncovering the mysteries of the human genome suggest that long non-coding RNAs (lncRNAs) are important regulatory components. Although lncRNAs are known to affect gene transcription, their mechanisms and biological implications are still unclear. Experimental research has shown that lncRNA synthesis, subcellular localization, and interactions with macromolecules like DNA, other RNAs, or proteins can all have an impact on gene expression in various biological processes. In this review, we highlight and discuss the major mechanisms through which lncRNAs function as master regulators of the human genome. Specifically, the objective of our review is to examine how lncRNAs regulate different processes like cell division, cell cycle, and immune responses, and unravel their roles in maintaining genomic architecture and integrity.
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Affiliation(s)
- Siddhant Sharma
- Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Aicha Asma Houfani
- Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, 2185 E Mall, Vancouver, BC, V6T 1Z4, Canada
| | - Leonard J Foster
- Michael Smith Laboratories and Department of Biochemistry and Molecular Biology, University of British Columbia, 2185 E Mall, Vancouver, BC, V6T 1Z4, Canada.
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11
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Genedy HH, Humbert P, Laoulaou B, Le Moal B, Fusellier M, Passirani C, Le Visage C, Guicheux J, Lepeltier É, Clouet J. MicroRNA-targeting nanomedicines for the treatment of intervertebral disc degeneration. Adv Drug Deliv Rev 2024; 207:115214. [PMID: 38395361 DOI: 10.1016/j.addr.2024.115214] [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: 12/13/2023] [Revised: 02/09/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024]
Abstract
Low back pain stands as a pervasive global health concern, afflicting almost 80% of adults at some point in their lives with nearly 40% attributable to intervertebral disc degeneration (IVDD). As only symptomatic relief can be offered to patients there is a dire need for innovative treatments.Given the accumulating evidence that multiple microRNAs (miRs) are dysregulated during IVDD, they could have a huge potential against this debilitating condition. The way miRs can profoundly modulate signaling pathways and influence several cellular processes at once is particularly exciting to tackle this multifaceted disorder. However, miR delivery encounters extracellular and intracellular biological barriers. A promising technology to address this challenge is the vectorization of miRs within nanoparticles, providing both protection and enhancing their uptake within the scarce target cells of the degenerated IVD. This comprehensive review presents the diverse spectrum of miRs' connection with IVDD and demonstrates their therapeutic potential when vectorized in nanomedicines.
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Affiliation(s)
- Hussein H Genedy
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France; Univ Angers, INSERM, CNRS, MINT, SFR ICAT, F-49000 Angers, France
| | - Paul Humbert
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France
| | - Bilel Laoulaou
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France; Univ Angers, INSERM, CNRS, MINT, SFR ICAT, F-49000 Angers, France
| | - Brian Le Moal
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France; Univ Angers, INSERM, CNRS, MINT, SFR ICAT, F-49000 Angers, France
| | - Marion Fusellier
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France; Department of Diagnostic Imaging, CRIP, ONIRIS, College of Veterinary Medicine, Food Science and Engineering, Nantes F-44307, France
| | | | - Catherine Le Visage
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France
| | - Jérôme Guicheux
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France
| | - Élise Lepeltier
- Univ Angers, INSERM, CNRS, MINT, SFR ICAT, F-49000 Angers, France; Institut Universitaire de France (IUF), France.
| | - Johann Clouet
- Nantes Université, Oniris, CHU Nantes, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR1229, Nantes, France
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12
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LIU GANG, SHI LEI, WANG BIN, WU ZEHUI, ZHAO HAIYUAN, ZHAO TIANYU, SHI LIANGHUI. Role of oncogenic long noncoding RNA KCNQ1OT1 in colon cancer. Oncol Res 2024; 32:585-596. [PMID: 38361755 PMCID: PMC10865742 DOI: 10.32604/or.2023.029349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 09/05/2023] [Indexed: 02/17/2024] Open
Abstract
The role of lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in colon cancer involves various tumorigenic processes and has been studied widely. However, the mechanism by which it promotes colon cancer remains unclear. Retroviral vector pSEB61 was retrofitted in established HCT116-siKCN and SW480-siKCN cells to silence KCNQ1OT1. Cellular proliferation was measured using CCK8 assay, and flow cytometry (FCM) detected cell cycle changes. RNA sequencing (RNA-Seq) analysis showed differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to analyze enriched functions and signaling pathways. RT-qPCR, immunofluorescence, and western blotting were carried out to validate downstream gene expressions. The effects of tumorigenesis were evaluated in BALB/c nude mice by tumor xenografts. Our data revealed that the silencing of KCNQ1OT1 in HCT116 and SW480 cells slowed cell growth and decreased the number of cells in the G2/M phase. RNA-Seq analysis showed the data of DEGs enriched in various GO and KEGG pathways such as DNA replication and cell cycle. RT-qPCR, immunofluorescence, and western blotting confirmed downstream CCNE2 and PCNA gene expressions. HCT116-siKCN cells significantly suppressed tumorigenesis in BALB/c nude mice. Our study suggests that lncRNA KCNQ1OT1 may provide a promising therapeutic strategy for colon cancer.
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Affiliation(s)
- GANG LIU
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - LEI SHI
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - BIN WANG
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - ZEHUI WU
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - HAIYUAN ZHAO
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
| | - TIANYU ZHAO
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China
| | - LIANGHUI SHI
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China
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13
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Malgundkar SH, Tamimi Y. The pivotal role of long non-coding RNAs as potential biomarkers and modulators of chemoresistance in ovarian cancer (OC). Hum Genet 2024; 143:107-124. [PMID: 38276976 DOI: 10.1007/s00439-023-02635-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 12/14/2023] [Indexed: 01/27/2024]
Abstract
Ovarian cancer (OC) is a fatal gynecological disease that is often diagnosed at later stages due to its asymptomatic nature and the absence of efficient early-stage biomarkers. Previous studies have identified genes with abnormal expression in OC that couldn't be explained by methylation or mutation, indicating alternative mechanisms of gene regulation. Recent advances in human transcriptome studies have led to research on non-coding RNAs (ncRNAs) as regulators of cancer gene expression. Long non-coding RNAs (lncRNAs), a class of ncRNAs with a length greater than 200 nucleotides, have been identified as crucial regulators of physiological processes and human diseases, including cancer. Dysregulated lncRNA expression has also been found to play a crucial role in ovarian carcinogenesis, indicating their potential as novel and non-invasive biomarkers for improving OC management. However, despite the discovery of several thousand lncRNAs, only one has been approved for clinical use as a biomarker in cancer, highlighting the importance of further research in this field. In addition to their potential as biomarkers, lncRNAs have been implicated in modulating chemoresistance, a major problem in OC. Several studies have identified altered lncRNA expression upon drug treatment, further emphasizing their potential to modulate chemoresistance. In this review, we highlight the characteristics of lncRNAs, their function, and their potential to serve as tumor markers in OC. We also discuss a few databases providing detailed information on lncRNAs in various cancer types. Despite the promising potential of lncRNAs, further research is necessary to fully understand their role in cancer and develop effective strategies to combat this devastating disease.
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Affiliation(s)
- Shika Hanif Malgundkar
- Biochemistry Department, College of Medicine and Health Sciences, Sultan Qaboos University, PC 123, PO Box 35, Muscat, Sultanate of Oman
| | - Yahya Tamimi
- Biochemistry Department, College of Medicine and Health Sciences, Sultan Qaboos University, PC 123, PO Box 35, Muscat, Sultanate of Oman.
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14
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Beatriz Cristina Biz T, Carolina de Sousa CS, Frank John S, Miriam Galvonas J. LncRNAs in melanoma phenotypic plasticity: emerging targets for promising therapies. RNA Biol 2024; 21:81-93. [PMID: 39498940 PMCID: PMC11540095 DOI: 10.1080/15476286.2024.2421672] [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] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/07/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) have received growing attention due to their diverse regulatory roles in cancer, including in melanoma, an aggressive type of skin cancer. The plasticity and phenotypic adaptability of melanoma cells are crucial factors contributing to therapeutic resistance. The identification of molecules playing key roles in melanoma cell plasticity could unravel novel and more effective therapeutic targets. This review presents current concepts of melanoma cell plasticity, illustrating its fluidity and dismissing the outdated notion of epithelial-mesenchymal-like transition as a simplistic binary process. Emphasis is placed on the pivotal role of lncRNAs in orchestrating cell plasticity, employing various mechanisms recently elucidated and unveiling their potential as promising targets for novel therapeutic strategies. Insights into the molecular mechanisms coordinated by lncRNAs in melanoma pave the way for the development of RNA-based therapies, holding great promise for enhancing treatment outcomes and offering a glimpse into a more effective approach to melanoma treatment.
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Affiliation(s)
- Tonin Beatriz Cristina Biz
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Slack Frank John
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Jasiulionis Miriam Galvonas
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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15
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Peng PH, Chen JL, Wu HH, Yang WH, Lin LJ, Lai JCY, Chang JS, Syu JL, Wu HT, Hsu FT, Cheng WC, Hsu KW. Interplay between lncRNA RP11-367G18.1 variant 2 and YY1 plays a vital role in hypoxia-mediated gene expression and tumorigenesis. Cancer Cell Int 2023; 23:266. [PMID: 37941005 PMCID: PMC10634066 DOI: 10.1186/s12935-023-03067-6] [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: 04/08/2023] [Accepted: 09/15/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND The hypoxia-responsive long non-coding RNA, RP11-367G18.1, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the underlying molecular mechanism remains poorly understood. METHODS RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify RP11-367G18.1 variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of RP11-367G18.1 variant 2-YY1 complex on tumor progression. RESULTS In this study, RNA sequencing data revealed that hypoxia and RP11-367G18.1 variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an RP11-367G18.1 variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α. RP11-367G18.1 variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of RP11-367G18.1 and YY1 which were associated with poor patient outcomes. RP11-367G18.1 variant 2-YY1 complex contributes to hypoxia-induced epithelial-mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on RP11-367G18.1 variant 2. CONCLUSIONS RP11-367G18.1 variant 2-YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.
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Affiliation(s)
- Pei-Hua Peng
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan
| | - Ji-Lin Chen
- Comprehensive Breast Health Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih- Pai Road, Taipei, 112, Taiwan
| | - Heng-Hsiung Wu
- Research Center for Cancer Biology, China Medical University, Taichung, 40402, Taiwan
- Drug Development Center, Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 40402, Taiwan
| | - Wen-Hao Yang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan
| | - Li-Jie Lin
- Research Center for Cancer Biology, China Medical University, Taichung, 40402, Taiwan
- The PhD Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, 40402, Taiwan
| | - Joseph Chieh-Yu Lai
- Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan
| | - Jeng-Shou Chang
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, 333, Taiwan
| | - Jia-Ling Syu
- Research Center for Cancer Biology, China Medical University, Taichung, 40402, Taiwan
| | - Han-Tsang Wu
- Cancer Research Center, Changhua Christian Hospital, Changhua, 500, Taiwan
| | - Fei-Ting Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, 40402, Taiwan.
| | - Wei-Chung Cheng
- Research Center for Cancer Biology, China Medical University, Taichung, 40402, Taiwan.
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan.
- The PhD Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, 40402, Taiwan.
| | - Kai-Wen Hsu
- Research Center for Cancer Biology, China Medical University, Taichung, 40402, Taiwan.
- Drug Development Center, Program for Cancer Biology and Drug Discovery, China Medical University, Taichung, 40402, Taiwan.
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung, 40402, Taiwan.
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16
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Tang X, Li Q, Feng X, Yang B, Zhong X, Zhou Y, Wang Q, Mao Y, Xie W, Liu T, Tang Q, Guo W, Wu F, Feng X, Wang Q, Lu Y, Xu J. Identification and Functional Analysis of Drought-Responsive Long Noncoding RNAs in Maize Roots. Int J Mol Sci 2023; 24:15039. [PMID: 37894720 PMCID: PMC10606207 DOI: 10.3390/ijms242015039] [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: 07/25/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) are transcripts with lengths of more than 200 nt and limited protein-coding potential. They were found to play important roles in plant stress responses. In this study, the maize drought-tolerant inbred line AC7643 and drought-sensitive inbred line AC7729/TZSRW, as well as their recombinant inbred lines (RILs) were selected to identify drought-responsive lncRNAs in roots. Compared with non-responsive lncRNAs, drought-responsive lncRNAs had different sequence characteristics in length of genes and number of exons. The ratio of down-regulated lncRNAs induced by drought was significantly higher than that of coding genes; and lncRNAs were more widespread expressed in recombination sites in the RILs. Additionally, by integration of the modifications of DNA 5-methylcytidine (5mC), histones, and RNA N6-methyladenosine (m6A), it was found that the enrichment of histone modifications associated with transcriptional activation in the genes generated lncRNAs was lower that coding genes. The lncRNAs-mRNAs co-expression network, containing 15,340 coding genes and 953 lncRNAs, was constructed to investigate the molecular functions of lncRNAs. There are 13 modules found to be associated with survival rate under drought. We found nine SNPs located in lncRNAs among the modules associated with plant survival under drought. In conclusion, we revealed the characteristics of lncRNAs responding to drought in maize roots based on multiomics studies. These findings enrich our understanding of lncRNAs under drought and shed light on the complex regulatory networks that are orchestrated by the noncoding RNAs in response to drought stress.
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Affiliation(s)
- Xin Tang
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Qimeng Li
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiaoju Feng
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Bo Yang
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Xiu Zhong
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Yang Zhou
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Qi Wang
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Yan Mao
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Wubin Xie
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Tianhong Liu
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Qi Tang
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Wei Guo
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Fengkai Wu
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuanjun Feng
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Qingjun Wang
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Yanli Lu
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
| | - Jie Xu
- Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China; (X.T.); (Q.L.); (X.F.); (B.Y.); (X.Z.); (Y.Z.); (Q.W.); (Y.M.); (W.X.); (T.L.); (Q.T.); (W.G.); (F.W.); (X.F.); (Q.W.)
- State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University, Chengdu 611130, China
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17
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Chang CH, Cheng TY, Yeh WW, Luo YL, Campbell M, Kuo TC, Shen TW, Hong YC, Tsai CH, Peng YC, Pan CC, Yang MH, Shih JC, Kung HJ, Huang WJ, Chang PC, Lin TP. REST-repressed lncRNA LINC01801 induces neuroendocrine differentiation in prostate cancer via transcriptional activation of autophagy. Am J Cancer Res 2023; 13:3983-4002. [PMID: 37818052 PMCID: PMC10560947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/03/2023] [Indexed: 10/12/2023] Open
Abstract
The association between REST reduction and the development of neuroendocrine prostate cancer (NEPC), a novel drug-resistant and lethal variant of castration-resistant prostate cancer (CRPC), is well established. To better understand the mechanisms underlying this process, we aimed to identify REST-repressed long noncoding RNAs (lncRNAs) that promote neuroendocrine differentiation (NED), thus facilitating targeted therapy-induced resistance. In this study, we used data from REST knockdown RNA sequencing combined with siRNA screening to determine that LINC01801 was upregulated and played a crucial role in NED in prostate cancer (PCa). Using The Cancer Genome Atlas (TCGA) prostate adenocarcinoma database and CRPC samples collected in our laboratory, we demonstrated that LINC01801 expression is upregulated in NEPC. Functional experiments revealed that overexpression of LINC01801 had a slight stimulatory effect on the NED of LNCaP cells, while downregulation of LINC01801 significantly inhibited the induction of NED. Mechanistically, LINC01801 is transcriptionally repressed by REST, and transcriptomic analysis revealed that LINC01801 preferentially affects the autophagy pathway. LINC01801 was found to function as a competing endogenous RNA (ceRNA) to regulate the expression of autophagy-related genes by sponging hsa-miR-6889-3p in prostate cancer cells. In conclusion, our data expand the current knowledge of REST-induced NED and highlight the contribution of the REST-LINC01801-hsa-miR-6889-3p axis to autophagic induction, which may provide promising avenues for therapeutic opportunities.
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Affiliation(s)
- Ching-Hsin Chang
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
- Department of Urology, Taipei Medical University HospitalTaipei 11031, Taiwan
| | - Ting-Yu Cheng
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
| | - Wayne W Yeh
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
| | - Yun-Li Luo
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
| | - Mel Campbell
- Comprehensive Cancer Center, University of California at DavisSacramento, CA 95817, USA
| | - Tse-Chun Kuo
- Institute of Molecular and Genomic Medicine, National Health Research InstitutesZhunan, Miaoli 35053, Taiwan
| | - Tsai-Wen Shen
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
| | - Yung-Chih Hong
- Faculty of Medicine, National Yang Ming Chiao Tung UniversityTaipei 11221, Taiwan
| | - Cheng-Han Tsai
- Department of Urology, Taipei Veterans General HospitalTaipei 11217, Taiwan
| | - Yu-Ching Peng
- Department of Pathology and Laboratory Medicine, Taipei Veterans General HospitalTaipei 11217, Taiwan
| | - Chin-Chen Pan
- Department of Pathology and Laboratory Medicine, Taipei Veterans General HospitalTaipei 11217, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung UniversityTaipei 11221, Taiwan
- Cancer Progression Research Center, National Yang Ming Chiao Tung UniversityTaipei 11221, Taiwan
| | - Jean-Chen Shih
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern CaliforniaLos Angeles, CA 90089, USA
| | - Hsing-Jien Kung
- Comprehensive Cancer Center, University of California at DavisSacramento, CA 95817, USA
- TMU Research Center of Cancer Translational Medicine, Taipei Medical UniversityTaipei 11031, Taiwan
| | - William J Huang
- Department of Urology, Taipei Veterans General HospitalTaipei 11217, Taiwan
| | - Pei-Ching Chang
- Institute of Microbiology and Immunology, National Yang Ming Chiao Tung UniversityHsinchu 30010, Taiwan
- Cancer Progression Research Center, National Yang Ming Chiao Tung UniversityTaipei 11221, Taiwan
| | - Tzu-Ping Lin
- Faculty of Medicine, National Yang Ming Chiao Tung UniversityTaipei 11221, Taiwan
- Department of Urology, Taipei Veterans General HospitalTaipei 11217, Taiwan
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18
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Zhang Y, Wang X, Zhang C, Yi H. The dysregulation of lncRNAs by epigenetic factors in human pathologies. Drug Discov Today 2023; 28:103664. [PMID: 37348827 DOI: 10.1016/j.drudis.2023.103664] [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: 12/23/2022] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/24/2023]
Abstract
Dysregulation of long noncoding RNAs (lncRNAs) contributes to numerous human diseases, including cancers and autoimmune diseases (ADs). Given the importance of lncRNAs in disease initiation and progression, a deeper understanding of their complex regulatory network is required to facilitate their use as therapeutic targets for ADs. In this review, we summarize how lncRNAs are dysregulated in pathological states by epigenetic factors, including RNA-binding proteins, chemical modifications (N6-methyladenosine, 5-methylcytosine, 7-methylguanosine, adenosine-to-inosine editing, microRNA, alternative splicing, DNA methylation, and histone modification). Moreover, the roles of lncRNA epigenetic regulators in immune response and ADs are discussed, providing new insights into the complicated epigenetic factor-lncRNA network, thus, laying a theoretical foundation for future research and clinical application of lncRNAs.
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Affiliation(s)
- Yanli Zhang
- Central Laboratory, The First Hospital of Jilin University, Changchun, Jilin, China; Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, Jilin 130021, China; Department of Echocardiography, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaocong Wang
- Department of Echocardiography, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chen Zhang
- Colorectal and Anal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huanfa Yi
- Central Laboratory, The First Hospital of Jilin University, Changchun, Jilin, China; Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, Changchun, Jilin 130021, China.
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19
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Batugedara G, Lu XM, Hristov B, Abel S, Chahine Z, Hollin T, Williams D, Wang T, Cort A, Lenz T, Thompson TA, Prudhomme J, Tripathi AK, Xu G, Cudini J, Dogga S, Lawniczak M, Noble WS, Sinnis P, Le Roch KG. Novel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum. Nat Commun 2023; 14:5086. [PMID: 37607941 PMCID: PMC10444892 DOI: 10.1038/s41467-023-40883-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 08/10/2023] [Indexed: 08/24/2023] Open
Abstract
The complex life cycle of Plasmodium falciparum requires coordinated gene expression regulation to allow host cell invasion, transmission, and immune evasion. Increasing evidence now suggests a major role for epigenetic mechanisms in gene expression in the parasite. In eukaryotes, many lncRNAs have been identified to be pivotal regulators of genome structure and gene expression. To investigate the regulatory roles of lncRNAs in P. falciparum we explore the intergenic lncRNA distribution in nuclear and cytoplasmic subcellular locations. Using nascent RNA expression profiles, we identify a total of 1768 lncRNAs, of which 718 (~41%) are novels in P. falciparum. The subcellular localization and stage-specific expression of several putative lncRNAs are validated using RNA-FISH. Additionally, the genome-wide occupancy of several candidate nuclear lncRNAs is explored using ChIRP. The results reveal that lncRNA occupancy sites are focal and sequence-specific with a particular enrichment for several parasite-specific gene families, including those involved in pathogenesis and sexual differentiation. Genomic and phenotypic analysis of one specific lncRNA demonstrate its importance in sexual differentiation and reproduction. Our findings bring a new level of insight into the role of lncRNAs in pathogenicity, gene regulation and sexual differentiation, opening new avenues for targeted therapeutic strategies against the deadly malaria parasite.
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Affiliation(s)
- Gayani Batugedara
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Xueqing M Lu
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Borislav Hristov
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA
| | - Steven Abel
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Zeinab Chahine
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Thomas Hollin
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Desiree Williams
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Tina Wang
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Anthony Cort
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Todd Lenz
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Trevor A Thompson
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Jacques Prudhomme
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Abhai K Tripathi
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Guoyue Xu
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | | | - Sunil Dogga
- Wellcome Sanger Institute, Hinxton, CB10 1SA, UK
| | | | | | - Photini Sinnis
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Karine G Le Roch
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA.
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20
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Chen H, Zhang M, Deng Y. Long Noncoding RNAs in Taxane Resistance of Breast Cancer. Int J Mol Sci 2023; 24:12253. [PMID: 37569629 PMCID: PMC10418730 DOI: 10.3390/ijms241512253] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/25/2023] [Accepted: 07/29/2023] [Indexed: 08/13/2023] Open
Abstract
Breast cancer is a common cancer in women and a leading cause of mortality. With the early diagnosis and development of therapeutic drugs, the prognosis of breast cancer has markedly improved. Chemotherapy is one of the predominant strategies for the treatment of breast cancer. Taxanes, including paclitaxel and docetaxel, are widely used in the treatment of breast cancer and remarkably decrease the risk of death and recurrence. However, taxane resistance caused by multiple factors significantly impacts the effect of the drug and leads to poor prognosis. Long noncoding RNAs (lncRNAs) have been shown to play a significant role in critical cellular processes, and a number of studies have illustrated that lncRNAs play vital roles in taxane resistance. In this review, we systematically summarize the mechanisms of taxane resistance in breast cancer and the functions of lncRNAs in taxane resistance in breast cancer. The findings provide insight into the role of lncRNAs in taxane resistance and suggest that lncRNAs may be used to develop therapeutic targets to prevent or reverse taxane resistance in patients with breast cancer.
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Affiliation(s)
- Hailong Chen
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Mengwen Zhang
- Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Yongchuan Deng
- Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
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21
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Ranjbar M, Heydarzadeh S, Shekari Khaniani M, Foruzandeh Z, Seif F, Pornour M, Rahmanpour D, Tarhriz V, Alivand M. Mutual interaction of lncRNAs and epigenetics: focusing on cancer. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023. [DOI: 10.1186/s43042-023-00404-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023] Open
Abstract
AbstractLong noncoding RNAs are characterized as noncoding transcripts longer than 200 nucleotides in response to a variety of functions within the cells. They are involved in almost all cellular mechanisms so as epigenetics. Given that epigenetics is an important phenomenon, which participates in the biology of complex diseases, many valuable studies have been performed to demonstrate the control status of lncRNAs and epigenetics. DNA methylation and histone modifications as epigenetic mechanisms can regulate the expression of lncRNAs by affecting their coding genes. Reciprocally, the three-dimensional structure of lncRNAs could mechanistically control the activity of epigenetic-related enzymes. Dysregulation in the mutual interaction between epigenetics and lncRNAs is one of the hallmarks of cancer. These mechanisms are either directly or indirectly involved in various cancer properties such as proliferation, apoptosis, invasion, and metastasis. For instance, lncRNA HOTAIR plays a role in regulating the expression of many genes by interacting with epigenetic factors such as DNA methyltransferases and EZH2, and thus plays a role in the initiation and progression of various cancers. Conversely, the expression of this lncRNA is also controlled by epigenetic factors. Therefore, focusing on this reciprocated interaction can apply to cancer management and the identification of prognostic, diagnostic, and druggable targets. In the current review, we discuss the reciprocal relationship between lncRNAs and epigenetic mechanisms to promote or prevent cancer progression and find new potent biomarkers and targets for cancer diagnosis and therapy.
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22
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Islam S, Mukherjee C. Molecular regulation of hypoxia through the lenses of noncoding RNAs and epitranscriptome. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1750. [PMID: 35785444 DOI: 10.1002/wrna.1750] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 05/27/2022] [Accepted: 06/06/2022] [Indexed: 11/09/2022]
Abstract
Cells maintain homeostasis in response to environmental stress through specific cell stress responses. Hypoxic stress, well known to be associated with diverse solid tumors, is one of the main reasons for cancer-related mortality. Although cells can balance themselves well during hypoxic stress, the underlying molecular mechanisms are not well understood. The enhanced appreciation of diverse roles played by noncoding transcriptome and epigenome in recent years has brought to light the involvement of noncoding RNAs and epigenetic modifiers in hypoxic regulation. The emergence of techniques like deep sequencing has facilitated the identification of large numbers of long noncoding RNAs (lncRNAs) that are differentially regulated in various cancers. Similarly, proteomic studies have identified diverse epigenetic modifiers such as HATs, HDACs, DNMTs, polycomb groups of proteins, and their possible roles in the regulation of hypoxia. The crosstalk between lncRNAs and epigenetic modifiers play a pivotal role in hypoxia-induced cancer initiation and progression. Besides the lncRNAs, several other noncoding RNAs like circular RNAs, miRNAs, and so forth are also expressed during hypoxic conditions. Hypoxia has a profound effect on the expression of noncoding RNAs and epigenetic modifiers. Conversely, noncoding RNAs/epigenetic modifies can regulate the hypoxia signaling axis by modulating the stability of the hypoxia-inducible factors (HIFs). The focus of this review is to illustrate the molecular orchestration underlying hypoxia biology, especially in cancers, which can help in identifying promising therapeutic targets in hypoxia-induced cancers. This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry.
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Affiliation(s)
- Safirul Islam
- Institute of Health Sciences (erstwhile School of Biotechnology), Presidency University, Kolkata, India
| | - Chandrama Mukherjee
- Institute of Health Sciences (erstwhile School of Biotechnology), Presidency University, Kolkata, India
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23
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Shao IH, Peng PH, Wu HH, Chen JL, Lai JCY, Chang JS, Wu HT, Wu KJ, Pang ST, Hsu KW. RP11-367G18.1 V2 enhances clear cell renal cell carcinoma progression via induction of epithelial-mesenchymal transition. Cancer Med 2023; 12:9788-9801. [PMID: 36847128 PMCID: PMC10166984 DOI: 10.1002/cam4.5723] [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: 08/14/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 03/01/2023] Open
Abstract
PURPOSE Metastasis is the end stage of renal cell carcinoma (RCC), and clear cell renal cell carcinoma (ccRCC) is the most common malignant subtype. The hypoxic microenvironment is a common feature in ccRCC and plays an essential role in the regulation of epithelial-mesenchymal transition (EMT). Accumulating evidence manifests that long non-coding RNAs (lncRNAs) participate in RCC tumorigenesis and regulate hypoxia-induced EMT. Here, we identified a lncRNA RP11-367G18.1 induced by hypoxia, that was overexpressed in ccRCC tissues. METHODS A total of 216 specimens, including 149 ccRCC tumor samples and 67 related normal kidney parenchyma tissue samples, were collected. To investigate the biological fucntions of RP11.367G18.1 in ccRCC, migration, invasion, soft agar colony formation, xenograft tumorigenicity assays, and tail vein and orthotopic metastatic mouse models were performed. The relationship between RP11-367G18.1 and downstream signaling was analyzed utilizing reporter assay, RNA pull-down, chromatin immunopreciptation, and chromatin isolation by RNA purification assays. RESULTS Hypoxic conditions and overexpression of HIF-1α increased the level of RP11-367G18.1. RP11-367G18.1 induced EMT and enhanced cell migration and invasion through variant 2. Inhibition of RP11-367G18.1 variant 2 reversed hypoxia-induced EMT phenotypes. An in vivo study revealed that RP11-367G18.1 variant 2 was required for hypoxia-induced tumor growth and metastasis in ccRCC. Mechanistically, RP11-367G18.1 variant 2 interacted with p300 histone acetyltransferase to regulate lysine 16 acetylation on histone 4 (H4K16Ac), thus contributing to hypoxia-regulated gene expression. Clinically, RP11-367G18.1 variant 2 was upregulated in ccRCC tissues, particularly metastatic ccRCC tissues, and it is linked to poor overall survival. CONCLUSION These findings demonstrate the prognostic value and EMT-promoting role of RP11-367G18.1 and indicate that this lncRNA may provide a therapeutic target for ccRCC.
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Affiliation(s)
- I-Hung Shao
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Pei-Hua Peng
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Heng-Hsiung Wu
- Research Center for Cancer Biology, China Medical University, Taichung City, Taiwan.,Program for Cancer Biology and Drug Discovery, China Medical University, Taichung City, Taiwan.,Drug Development Center, China Medical University, Taichung City, Taiwan
| | - Ji-Lin Chen
- Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | - Jeng-Shou Chang
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Han-Tsang Wu
- Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan
| | - Kou-Juey Wu
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.,Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
| | - See-Tong Pang
- Cancer Genome Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kai-Wen Hsu
- Research Center for Cancer Biology, China Medical University, Taichung City, Taiwan.,Drug Development Center, China Medical University, Taichung City, Taiwan.,Institute of Translational Medicine and New Drug Development, China Medical University, Taichung City, Taiwan
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24
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Li Z, Fang Y, Zhang Y, Zhou X. RNA-seq analysis of differentially expressed LncRNAs from leishmaniasis patients compared to uninfected humans. Acta Trop 2023; 238:106738. [PMID: 36379256 DOI: 10.1016/j.actatropica.2022.106738] [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: 06/07/2022] [Revised: 10/02/2022] [Accepted: 10/31/2022] [Indexed: 11/14/2022]
Abstract
Leishmaniasis is a parasitic disease that seriously endangers human health. Furthermore, among the parasitic diseases, leishmaniasis is the third most common cause of death after malaria and schistosomiasis. However, the potential function of LncRNAs in leishmaniasis remain unclear. This study aimed to explore the differentially expressed LncRNAs in leishmaniasis. The sera of leishmaniasis patients and uninfected persons for controls were obtained and analyzed by high-throughput sequencing. Moreover, the expression of key LncRNAs was detected by qPCR. The results showed that 970 differentially expressed LncRNAs and 1692 differentially expressed mRNAs were screened compared to control groups. Then, 520 target genes were identified by using bioinformation analysis and the ENCORI database. The bioinformatics analysis revealed that the differentially expressed target genes were enriched in autophagy animal, FoxO signaling pathway, mTOR signaling pathway, and apoptosis, et al. Among those differentially expressed LncRNAs, nine key LncRNAs were selected (MALAT1, NUTM2A-AS1, and LINC00963 had high expression; LINC00622, MAPKAPK5-AS1, LINC02289, XPC-AS1, ZFAS1 and SNHG5 had low expression) by qPCR. This study suggests that different expressions of LncRNAs may involve in the potential function in leishmaniasis and provide a novel insight for diagnosis of this zoonotic disease.
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Affiliation(s)
- Zhongqiu Li
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
| | - Yuan Fang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yi Zhang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
| | - Xiaonong Zhou
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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25
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Farzaneh M, Najafi S, Anbiyaee O, Azizidoost S, Khoshnam SE. LncRNA MALAT1-related signaling pathways in osteosarcoma. CLINICAL & TRANSLATIONAL ONCOLOGY : OFFICIAL PUBLICATION OF THE FEDERATION OF SPANISH ONCOLOGY SOCIETIES AND OF THE NATIONAL CANCER INSTITUTE OF MEXICO 2023; 25:21-32. [PMID: 35790599 DOI: 10.1007/s12094-022-02876-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/10/2022] [Indexed: 01/07/2023]
Abstract
Osteosarcoma (OS) is a common and malignant form of bone cancer, which affects children and young adults. OS is identified by osteogenic differentiation and metastasis. However, the exact molecular mechanism of OS development and progression is still unclear. Recently, long non-coding RNAs (lncRNA) have been proven to regulate OS proliferation and drug resistance. LncRNAs are longer than 200 nucleotides that represent the extensive applications in the processing of pre-mRNA and the pathogenesis of human diseases. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) is a well-known lncRNA known as a transcriptional and translational regulator. The aberrant expression of MALAT1 has been shown in several human cancers. The high level of MALAT1 is involved in OS cell growth and tumorigenicity by targeting several signaling pathways and miRNAs. Hence, MALAT1 might be a suitable approach for OS diagnosis and treatment. In this review, we will summarize the role of lncRNA MALAT1 in the pathophysiology of OS.
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Affiliation(s)
- Maryam Farzaneh
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Omid Anbiyaee
- School of Medicine, Cardiovascular Research Center, Nemazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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26
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Wang E, Wang H, Chakrabarti S. Endothelial-to-mesenchymal transition: An underappreciated mediator of diabetic complications. Front Endocrinol (Lausanne) 2023; 14:1050540. [PMID: 36777351 PMCID: PMC9911675 DOI: 10.3389/fendo.2023.1050540] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/17/2023] [Indexed: 01/28/2023] Open
Abstract
Diabetes and its complications represent a great burden on the global healthcare system. Diabetic complications are fundamentally diseases of the vasculature, with endothelial cells being the centerpiece of early hyperglycemia-induced changes. Endothelial-to-mesenchymal transition is a tightly regulated process that results in endothelial cells losing endothelial characteristics and developing mesenchymal traits. Although endothelial-to-mesenchymal transition has been found to occur within most of the major complications of diabetes, it has not been a major focus of study or a common target in the treatment or prevention of diabetic complications. In this review we summarize the importance of endothelial-to-mesenchymal transition in each major diabetic complication, examine specific mechanisms at play, and highlight potential mechanisms to prevent endothelial-to-mesenchymal transition in each of the major chronic complications of diabetes.
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27
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Yang Z, Xu F, Teschendorff AE, Zhao Y, Yao L, Li J, He Y. Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation. Front Mol Biosci 2022; 9:1067406. [PMID: 36533073 PMCID: PMC9755597 DOI: 10.3389/fmolb.2022.1067406] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/17/2022] [Indexed: 09/12/2023] Open
Abstract
DNA methylation is one of the most important epigenetic mechanisms that governing regulation of gene expression, aberrant DNA methylation patterns are strongly associated with human malignancies. Long non-coding RNAs (lncRNAs) have being discovered as a significant regulator on gene expression at the epigenetic level. Emerging evidences have indicated the intricate regulatory effects between lncRNAs and DNA methylation. On one hand, transcription of lncRNAs are controlled by the promoter methylation, which is similar to protein coding genes, on the other hand, lncRNA could interact with enzymes involved in DNA methylation to affect the methylation pattern of downstream genes, thus regulating their expression. In addition, circular RNAs (circRNAs) being an important class of noncoding RNA are also found to participate in this complex regulatory network. In this review, we summarize recent research progress on this crosstalk between lncRNA, circRNA, and DNA methylation as well as their potential functions in complex diseases including cancer. This work reveals a hidden layer for gene transcriptional regulation and enhances our understanding for epigenetics regarding detailed mechanisms on lncRNA regulatory function in human cancers.
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Affiliation(s)
- Zhen Yang
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Feng Xu
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Andrew E. Teschendorff
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yi Zhao
- Institute of Computing Technology, Chinese Academy of Sciences, Beijing, China
| | - Lei Yao
- Experiment Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jian Li
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yungang He
- Center for Medical Research and Innovation of Pudong Hospital, The Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
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28
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Endothelial derived miRNA-9 mediated cardiac fibrosis in diabetes and its regulation by ZFAS1. PLoS One 2022; 17:e0276076. [PMID: 36240130 PMCID: PMC9565427 DOI: 10.1371/journal.pone.0276076] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/28/2022] [Indexed: 11/07/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is one of the most prevalent causes of morbidity and mortality in diabetic patients. Hyperglycemia induces increased expression/deposition of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (Col) and plays an important role in fibrosis in diabetic cardiomyopathy (DCM). The roles of RNAs including microRNA (miRNA) and long non-coding RNAs (lncRNA) have begun to be understood in many conditions. In this study, we investigated the role of a specific miRNA, miR-9, and its interactions with lncRNA ZFAS1 in mediating fibrosis in DCM. Treatment with 25 mM glucose (HG) decreased miR-9 expression and increased expressions of ZFAS1, ECM proteins and inflammatory markers, compared to 5 mM glucose (NG) in the HCMECs by using qRT-PCR. Glucose-induced upregulation of ECM proteins can be prevented by ZFAS1 siRNA or miR-9 mimic transfection. Luciferase assay was confirmed miR-9 binding to FN 3’-UTR. miR-9 expression can be regulated by ZFAS1 through polycomb repressive complex 2 (PRC2) components using RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. In the in vivo experiment, hyperglycemia-induced the ECM production can be prevented by the miR-9 overexpression in the fibrosis in DCM. These studies showed a novel glucose-induced molecular mechanism in which ZFAS1 participates in the transcriptional regulation of ECM protein production in diabetes through miR-9.
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29
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de Almeida BC, dos Anjos LG, Dobroff AS, Baracat EC, Yang Q, Al-Hendy A, Carvalho KC. Epigenetic Features in Uterine Leiomyosarcoma and Endometrial Stromal Sarcomas: An Overview of the Literature. Biomedicines 2022; 10:2567. [PMID: 36289829 PMCID: PMC9599831 DOI: 10.3390/biomedicines10102567] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 10/04/2022] [Accepted: 10/06/2022] [Indexed: 11/16/2022] Open
Abstract
There is a consensus that epigenetic alterations play a key role in cancer initiation and its biology. Studies evaluating the modification in the DNA methylation and chromatin remodeling patterns, as well as gene regulation profile by non-coding RNAs (ncRNAs) have led to the development of novel therapeutic approaches to treat several tumor types. Indeed, despite clinical and translational challenges, combinatorial therapies employing agents targeting epigenetic modifications with conventional approaches have shown encouraging results. However, for rare neoplasia such as uterine leiomyosarcomas (LMS) and endometrial stromal sarcomas (ESS), treatment options are still limited. LMS has high chromosomal instability and molecular derangements, while ESS can present a specific gene fusion signature. Although they are the most frequent types of "pure" uterine sarcomas, these tumors are difficult to diagnose, have high rates of recurrence, and frequently develop resistance to current treatment options. The challenges involving the management of these tumors arise from the fact that the molecular mechanisms governing their progression have not been entirely elucidated. Hence, to fill this gap and highlight the importance of ongoing and future studies, we have cross-referenced the literature on uterine LMS and ESS and compiled the most relevant epigenetic studies, published between 2009 and 2022.
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Affiliation(s)
- Bruna Cristine de Almeida
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 05403-010, Brazil
| | - Laura Gonzalez dos Anjos
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 05403-010, Brazil
| | - Andrey Senos Dobroff
- UNM Comprehensive Cancer Center (UNMCCC), University of New Mexico, Albuquerque, NM 87131, USA
- Division of Molecular Medicine, Department of Internal Medicine, (UNM) School of Medicine, UNM Health Sciences Center, 1 University of New Mexico, Albuquerque, NM 87131, USA
| | - Edmund Chada Baracat
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 05403-010, Brazil
| | - Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Katia Candido Carvalho
- Laboratório de Ginecologia Estrutural e Molecular (LIM 58), Disciplina de Ginecologia, Departamento de Obstetricia e Ginecologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo (HCFMUSP), São Paulo 05403-010, Brazil
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Hu XQ, Zhang XC, Li ST, Hua T. Construction and validation of a histone acetylation-related lncRNA prognosis signature for ovarian cancer. Front Genet 2022; 13:934246. [PMID: 36313424 PMCID: PMC9596759 DOI: 10.3389/fgene.2022.934246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Ovarian cancer (OC) leads to the most deaths among gynecological malignancies. The various epigenetic regulatory mechanisms of histone acetylation in cancer have attracted increasing attention from scientists. Long non-coding RNA (lncRNA) also plays an important role in multiple biology processes linked to OC. This study aimed to identify the histone acetylation-related lncRNAs (HARlncRNAs) with respect to the prognosis in OC. We obtained the transcriptome data from Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA); HARlncRNAs were first identified by co-expression and differential expression analyses, and then univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) were used to construct the HARlncRNAs risk signature. Kaplan–Meier analysis, time-dependent receiver operating characteristics (ROC), univariate Cox regression, multivariate Cox regression, nomogram, and calibration were conducted to verify and evaluate the risk signature. Gene set enrichment analysis (GSEA) in risk groups were conducted to explore the tightly correlated pathways with the risk group. A risk signature with 14 HARlncRNAs in OC was finally established and further validated in the International Cancer Genome Consortium (ICGC) cohort; the 1-, 3-, and 5-year ROC value, nomogram, and calibration results confirmed the good prediction power of this model. The patients were grouped into high- and low-risk subgroups according to the risk score by the median value. The low-risk group patients exhibited a higher homologous recombination deficiency (HRD) score, LOH_frac_altered, and mutLoad_nonsilent. Furthermore, consensus clustering analysis was employed to divide OC patients into three clusters based on the expression of the 14 HARlncRNAs, which presented different survival probabilities. Principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE) were also performed to evaluate the three clusters. In conclusion, the risk signature composed of 14 HARlncRNAs might function as biomarkers and prognostic indicators with respect to predicting the response to the anti-cancer drugs in OC.
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Affiliation(s)
- Xiao-Qian Hu
- Department of Oncology, Affiliated Xingtai People Hospital of Hebei Medical University, Xingtai, China
| | - Xiao-Chong Zhang
- Department of Oncology, Affiliated Xingtai People Hospital of Hebei Medical University, Xingtai, China
| | - Shao-Teng Li
- Department of Oncology, Affiliated Xingtai People Hospital of Hebei Medical University, Xingtai, China
| | - Tian Hua
- Department of Gynecology, Affiliated Xingtai People Hospital of Hebei Medical University, Xingtai, China
- *Correspondence: Tian Hua,
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Peña-Flores JA, Bermúdez M, Ramos-Payán R, Villegas-Mercado CE, Soto-Barreras U, Muela-Campos D, Álvarez-Ramírez A, Pérez-Aguirre B, Larrinua-Pacheco AD, López-Camarillo C, López-Gutiérrez JA, Garnica-Palazuelos J, Estrada-Macías ME, Cota-Quintero JL, Barraza-Gómez AA. Emerging role of lncRNAs in drug resistance mechanisms in head and neck squamous cell carcinoma. Front Oncol 2022; 12:965628. [PMID: 35978835 PMCID: PMC9376329 DOI: 10.3389/fonc.2022.965628] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) originates in the squamous cell lining the mucosal surfaces of the head and neck region, including the oral cavity, nasopharynx, tonsils, oropharynx, larynx, and hypopharynx. The heterogeneity, anatomical, and functional characteristics of the patient make the HNSCC a complex and difficult-to-treat disease, leading to a poor survival rate and a decreased quality of life due to the loss of important physiologic functions and aggressive surgical injury. Alteration of driver-oncogenic and tumor-suppressing lncRNAs has recently been recently in HNSCC to obtain possible biomarkers for diagnostic, prognostic, and therapeutic approaches. This review provides current knowledge about the implication of lncRNAs in drug resistance mechanisms in HNSCC. Chemotherapy resistance is a major therapeutic challenge in HNSCC in which lncRNAs are implicated. Lately, it has been shown that lncRNAs involved in autophagy induced by chemotherapy and epithelial-mesenchymal transition (EMT) can act as mechanisms of resistance to anticancer drugs. Conversely, lncRNAs involved in mesenchymal-epithelial transition (MET) are related to chemosensitivity and inhibition of invasiveness of drug-resistant cells. In this regard, long non-coding RNAs (lncRNAs) play a pivotal role in both processes and are important for cancer detection, progression, diagnosis, therapy response, and prognostic values. As the involvement of more lncRNAs is elucidated in chemoresistance mechanisms, an improvement in diagnostic and prognostic tools could promote an advance in targeted and specific therapies in precision oncology.
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Affiliation(s)
- José A. Peña-Flores
- Faculty of Odontology, Autonomous University of Chihuahua, Chihuahua, Mexico
| | - Mercedes Bermúdez
- Faculty of Odontology, Autonomous University of Chihuahua, Chihuahua, Mexico
| | - Rosalío Ramos-Payán
- Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Culiacán, Mexico
| | | | - Uriel Soto-Barreras
- Faculty of Odontology, Autonomous University of Chihuahua, Chihuahua, Mexico
| | | | | | | | | | | | - Jorge A. López-Gutiérrez
- Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Culiacán, Mexico
- Faculty of Biology, Autonomous University of Sinaloa, Culiacán, Mexico
| | | | | | - Juan L. Cota-Quintero
- Faculty of Biology, Autonomous University of Sinaloa, Culiacán, Mexico
- Faculty of Odontology , Autonomous University of Sinaloa, Culiacán, Mexico
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Pathania AS, Prathipati P, Pandey MK, Byrareddy SN, Coulter DW, Gupta SC, Challagundla KB. The emerging role of non-coding RNAs in the epigenetic regulation of pediatric cancers. Semin Cancer Biol 2022; 83:227-241. [PMID: 33910063 DOI: 10.1016/j.semcancer.2021.04.015] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 02/09/2023]
Abstract
Epigenetics is a process that involves the regulation of gene expression without altering the sequence of DNA. Numerous studies have documented that epigenetic mechanisms play a critical role in cell growth, differentiation, and cancer over the past decade. The well-known epigenetic modifications are either on DNA or at the histone proteins. Although several studies have focused on regulating gene expression by non-coding RNAs, the current understanding of their biological functions in various human diseases, particularly in cancers, is inadequate. Only about two percent of DNA is involved in coding the protein-coding genes, and leaving the rest 98 percent is non-coding and the scientific community regarded as junk or noise with no known purpose. Most non-coding RNAs are derived from such junk DNA and are known to be involved in various signaling pathways involving cancer initiation, progression, and the development of therapy resistance in many human cancer types. Recent studies have suggested that non-coding RNAs, especially microRNAs, piwi-interactingRNAs, and long non-coding RNAs, play a significant role in controlling epigenetic mechanism(s), indicating the potential effect of epigenetic modulation of non-coding RNAs on cancer progression. In this review article, we briefly presented epigenetic marks' characteristics, crosstalk between epigenetic modifications and microRNAs, piwi-interactingRNAs, and long non-coding RNAs to uncover the effect on the phenotype of pediatric cancers. Further, current knowledge on understanding the RNA epigenetics will help design novel therapeutics that target epigenetic regulatory networks to benefit cancer patients in the clinic.
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Affiliation(s)
- Anup S Pathania
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Philip Prathipati
- Laboratory of Bioinformatics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Manoj K Pandey
- Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ 08103, USA
| | - Siddappa N Byrareddy
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Don W Coulter
- Department of Pediatrics, Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Subash C Gupta
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
| | - Kishore B Challagundla
- Department of Biochemistry and Molecular Biology & The Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; The Children's Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Huang J, Zhang J, Xiao H. Identification of Epigenetic-Dysregulated lncRNAs Signature in Osteosarcoma by Multi-Omics Data Analysis. Front Med (Lausanne) 2022; 9:892593. [PMID: 35783605 PMCID: PMC9243510 DOI: 10.3389/fmed.2022.892593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundAlterations of epigenetic modification patterns are potential markers of cancer. The current study characterized six histone modifications in osteosarcoma and identified epigenetically dysregulated long non-coding RNAs (epi-lncRNAs).MethodsMulti-omics data were obtained from osteosarcoma cell line SJSA1 and a normal cell line. Differentially expressed lncRNAs (DElncRNAs) between osteosarcoma and normal skeletal muscle were analyzed using Limma. MACS2 was applied to identify the “peaks” modified by each histone in the cell. Promoters or enhancers of DElncRNA were overlapped with differential histone-modified regions (DHMR) to screen epi-lncRNAs. Univariate and multivariate Cox regression analysis were performed to detect the genes closely related to the prognosis of osteosarcoma and to construct risk models.ResultsA total of 17 symbolic epi-lncRNA in osteosarcoma were screened, and 13 of them were differentially expressed between osteosarcoma and normal samples. Eight epi-lncRNAs were retained by Univariate Cox regression analysis. Four of these epi-lncRNAs were used to construct an epi-lncRNA signature. The risk score of each osteosarcoma sample in the high- or low-risk group was estimated according to the epi-lncRNA signature. The overall survival (OS) of the low-risk group was significantly better than that of the high-risk group. The area under the receiver operating characteristic (ROC) curve of the model was 0.79 and 0.82 for 1-, 3-, and 5-year OS, respectively.ConclusionOur results revealed the histone modification pattern in osteosarcoma and developed 4-epi-lncRNA signature to predict the prognosis of osteosarcoma, laying a foundation for the identification of highly specific epigenetic biomarkers for osteosarcoma.
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Mallick AM, Tripathi A, Mishra S, Mukherjee A, Dutta C, Chatterjee A, Sinha Roy R. Emerging Approaches for Enabling RNAi Therapeutics. Chem Asian J 2022; 17:e202200451. [PMID: 35689534 DOI: 10.1002/asia.202200451] [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: 04/28/2022] [Revised: 06/04/2022] [Indexed: 11/07/2022]
Abstract
RNA interference (RNAi) is a primitive evolutionary mechanism developed to escape incorporation of foreign genetic material. siRNA has been instrumental in achieving the therapeutic potential of RNAi by theoretically silencing any gene of interest in a reversible and sequence-specific manner. Extrinsically administered siRNA generally needs a delivery vehicle to span across different physiological barriers and load into the RISC complex in the cytoplasm in its functional form to show its efficacy. This review discusses the designing principles and examples of different classes of delivery vehicles that have proved to be efficient in RNAi therapeutics. We also briefly discuss the role of RNAi therapeutics in genetic and rare diseases, epigenetic modifications, immunomodulation and combination modality to inch closer in creating a personalized therapy for metastatic cancer. At the end, we present, strategies and look into the opportunities to develop efficient delivery vehicles for RNAi which can be translated into clinics.
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Affiliation(s)
- Argha M Mallick
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Archana Tripathi
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Sukumar Mishra
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Asmita Mukherjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Chiranjit Dutta
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Present address:Department of Biological Sciences, NUS Environmental Research Institute (NERI), National University of Singapore (NUS), Block S2 #05-01, 16 Science Drive 4, Singapore, 117558, Singapore
| | - Ananya Chatterjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India
| | - Rituparna Sinha Roy
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741246, India.,Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India.,Centre for Climate and Environmental Studies, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
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da Paixão VF, Sosa OJ, da Silva Pellegrina DV, Dazzani B, Corrêa TB, Risério Bertoldi E, da Cruz E Alves-de-Moraes LB, de Oliveira Pessoa D, de Paiva Oliveira V, Alberto Chiong Zevallos R, Russo LC, Forti FL, Eduardo Ferreira J, Carioca Freitas H, Jukemura J, Machado MCC, Dirlei Begnami M, Setubal JC, Bassères DS, Moraes Reis E. Annotation and functional characterization of long noncoding RNAs deregulated in pancreatic adenocarcinoma. Cell Oncol (Dordr) 2022; 45:479-504. [PMID: 35567709 DOI: 10.1007/s13402-022-00678-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
PURPOSE Transcriptome analysis of pancreatic ductal adenocarcinoma (PDAC) has been useful to identify gene expression changes that sustain malignant phenotypes. Yet, most studies examined only tumor tissues and focused on protein-coding genes, leaving long non-coding RNAs (lncRNAs) largely underexplored. METHODS We generated total RNA-Seq data from patient-matched tumor and nonmalignant pancreatic tissues and implemented a computational pipeline to survey known and novel lncRNAs. siRNA-mediated knockdown in tumor cell lines was performed to assess the contribution of PDAC-associated lncRNAs to malignant phenotypes. Gene co-expression network and functional enrichment analyses were used to assign deregulated lncRNAs to biological processes and molecular pathways. RESULTS We detected 9,032 GENCODE lncRNAs as well as 523 unannotated lncRNAs, including transcripts significantly associated with patient outcome. Aberrant expression of a subset of novel and known lncRNAs was confirmed in patient samples and cell lines. siRNA-mediated knockdown of a subset of these lncRNAs (LINC01559, LINC01133, CCAT1, LINC00920 and UCA1) reduced cell proliferation, migration and invasion. Gene co-expression network analysis associated PDAC-deregulated lncRNAs with diverse biological processes, such as cell adhesion, protein glycosylation and DNA repair. Furthermore, UCA1 knockdown was shown to specifically deregulate co-expressed genes involved in DNA repair and to negatively impact DNA repair following damage induced by ionizing radiation. CONCLUSIONS Our study expands the repertoire of lncRNAs deregulated in PDAC, thereby revealing novel candidate biomarkers for patient risk stratification. It also provides a roadmap for functional assays aimed to characterize novel mechanisms of action of lncRNAs in pancreatic cancer, which could be explored for therapeutic development.
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Affiliation(s)
- Vinicius Ferreira da Paixão
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Omar Julio Sosa
- Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Bianca Dazzani
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Thalita Bueno Corrêa
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Ester Risério Bertoldi
- Programa Interunidades de Pós-Graduação em Bioinformática, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Luís Bruno da Cruz E Alves-de-Moraes
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Diogo de Oliveira Pessoa
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Victoria de Paiva Oliveira
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Ricardo Alberto Chiong Zevallos
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Lilian Cristina Russo
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Fabio Luis Forti
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - João Eduardo Ferreira
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - José Jukemura
- Departamento de Gastroenterologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | | | - Maria Dirlei Begnami
- Departamento de Anatomia Patológica - AC Camargo Cancer Center, São Paulo, SP, Brazil
| | - João Carlos Setubal
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Daniela Sanchez Bassères
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil
| | - Eduardo Moraes Reis
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cidade Universitária, São Paulo, SP, 05508-900, Brazil.
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Shan KS, Li WW, Ren W, Kong S, Peng LP, Zhuo HQ, Tian SB. LncRNA cancer susceptibility 20 regulates the metastasis of human gastric cancer cells via the miR-143-5p/MEMO1 molecular axis. World J Gastroenterol 2022; 28:1656-1670. [PMID: 35581960 PMCID: PMC9048782 DOI: 10.3748/wjg.v28.i16.1656] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/26/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is considered as one of the most widespread malignancies. Emerging evidence has shown that lncRNAs can function as important oncogenes or tumor suppressors during GC progression.
AIM To investigate the effect and mechanism of lncRNA cancer susceptibility 20 (CASC20) in the proliferation and metastasis of GC cells.
METHODS Data mining and clinical samples were used to evaluate the expression of CASC20 in GC and adjacent tissues. CASC20 was down-regulated in GC cells by short-interfering RNA. Cell proliferation was evaluated by CCK-8 assay, and cell migration and invasion were detected by wound healing and Transwell assays. The expressions of proteins related to epithelial-mesenchymal transition were detected by western blot assay.
RESULTS The expression of CASC20 was increased in GC tumor tissues and various GC cell lines. High CASC20 expression was correlated with a high risk of lymphatic metastasis and poor prognosis in GC patients. In vitro assays showed that silencing CASC20 reduced cell proliferation, migration, and invasion in GC cells. Mechanistic studies revealed that CASC20 exhibits oncogenic functions by regulating MEMO1 expression through competitive endogenous binding to miR-143-5p, leading to induction of epithelial-mesenchymal transition.
CONCLUSION Our findings indicate that CASC20 serves as a tumor promoter by regulating metastasis in GC via the miR-143-5p/MEMO1 axis. CASC20 may be a potential therapeutic target for GC.
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Affiliation(s)
- Ke-Shu Shan
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Wei-Wei Li
- Department of Critical Care Medicine, The 960th Hospital of the People's Liberation Army Joint Logistics Support Force, Jinan 250031, Shandong Province, China
| | - Wang Ren
- Department of General Surgery, People's Hospital of Sishui County, Jining 273200, Shandong Province, China
| | - Shuai Kong
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Li-Pan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Hong-Qing Zhuo
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
| | - Shu-Bo Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China
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Boda E, Lorenzati M, Parolisi R, Harding B, Pallavicini G, Bonfanti L, Moccia A, Bielas S, Di Cunto F, Buffo A. Molecular and functional heterogeneity in dorsal and ventral oligodendrocyte progenitor cells of the mouse forebrain in response to DNA damage. Nat Commun 2022; 13:2331. [PMID: 35484145 PMCID: PMC9051058 DOI: 10.1038/s41467-022-30010-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 04/07/2022] [Indexed: 11/09/2022] Open
Abstract
In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate either dorsal or ventral regions, where they present as transcriptionally and functionally equivalent cells. Despite that, developmental heterogeneity influences adult OPC responses upon demyelination. Here we show that accumulation of DNA damage due to ablation of citron-kinase or cisplatin treatment cell-autonomously disrupts OPC fate, resulting in cell death and senescence in the dorsal and ventral subsets, respectively. Such alternative fates are associated with distinct developmental origins of OPCs, and with a different activation of NRF2-mediated anti-oxidant responses. These data indicate that, upon injury, dorsal and ventral OPC subsets show functional and molecular diversity that can make them differentially vulnerable to pathological conditions associated with DNA damage.
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Affiliation(s)
- Enrica Boda
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy.
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy.
| | - Martina Lorenzati
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
| | - Roberta Parolisi
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
| | - Brian Harding
- Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Gianmarco Pallavicini
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
| | - Luca Bonfanti
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | - Amanda Moccia
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Stephanie Bielas
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Ferdinando Di Cunto
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
- Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy
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LncRNA-mediated DNA methylation: an emerging mechanism in cancer and beyond. J Exp Clin Cancer Res 2022; 41:100. [PMID: 35292092 PMCID: PMC8922926 DOI: 10.1186/s13046-022-02319-z] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023] Open
Abstract
DNA methylation is one of the most important epigenetic mechanisms to regulate gene expression, which is highly dynamic during development and specifically maintained in somatic cells. Aberrant DNA methylation patterns are strongly associated with human diseases including cancer. How are the cell-specific DNA methylation patterns established or disturbed is a pivotal question in developmental biology and cancer epigenetics. Currently, compelling evidence has emerged that long non-coding RNA (lncRNA) mediates DNA methylation in both physiological and pathological conditions. In this review, we provide an overview of the current understanding of lncRNA-mediated DNA methylation, with emphasis on the roles of this mechanism in cancer, which to the best of our knowledge, has not been systematically summarized. In addition, we also discuss the potential clinical applications of this mechanism in RNA-targeting drug development.
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Lift the curtain on long non-coding RNAs in hematological malignancies: Pathogenic elements and potential targets. Cancer Lett 2022; 536:215645. [DOI: 10.1016/j.canlet.2022.215645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/01/2022] [Accepted: 03/12/2022] [Indexed: 12/19/2022]
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LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival. Proc Natl Acad Sci U S A 2022; 119:2110428119. [PMID: 35091468 PMCID: PMC8812561 DOI: 10.1073/pnas.2110428119] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Here, we report that the long noncoding RNA lysosome cell death regulator (LCDR) mediates the survival of cancer cells, counteracting the effects of apoptosis triggered by lysosomal cell death pathways. Mechanistically, LCDR, as a cofactor for heterogenous nuclear ribonucleoprotein K (hnRNP K) to potentiate the stabilization of lysosomal membrane protein lysosomal-associated protein transmembrane 5 (LAPTM5), prevents lysosomal membrane permeabilization and promotes cancer cell survival. Clinically, LCDR, hnRNP K, and LAPTM5 are significantly up-regulated in lung adenocarcinoma (LUAD) patients. Targeting LCDR via nanoparticles-mediated RNA interference technology increases cell death in vitro and inhibits the growth of patient-derived xenografts of LUAD in vivo. Our study demonstrates that LCDR contributes to cancer pathology by regulating LCDR-mediated apoptosis. Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation–regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.
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Epigenetic Mechanisms in Understanding Nanomaterial-Induced Toxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1357:195-223. [DOI: 10.1007/978-3-030-88071-2_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Mbadhi MN, Tang JM, Zhang JX. Histone Lysine Methylation and Long Non-Coding RNA: The New Target Players in Skeletal Muscle Cell Regeneration. Front Cell Dev Biol 2021; 9:759237. [PMID: 34926450 PMCID: PMC8678087 DOI: 10.3389/fcell.2021.759237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/11/2021] [Indexed: 11/13/2022] Open
Abstract
Satellite stem cell availability and high regenerative capacity have made them an ideal therapeutic approach for muscular dystrophies and neuromuscular diseases. Adult satellite stem cells remain in a quiescent state and become activated upon muscular injury. A series of molecular mechanisms succeed under the control of epigenetic regulation and various myogenic regulatory transcription factors myogenic regulatory factors, leading to their differentiation into skeletal muscles. The regulation of MRFs via various epigenetic factors, including DNA methylation, histone modification, and non-coding RNA, determine the fate of myogenesis. Furthermore, the development of histone deacetylation inhibitors (HDACi) has shown promising benefits in their use in clinical trials of muscular diseases. However, the complete application of using satellite stem cells in the clinic is still not achieved. While therapeutic advancements in the use of HDACi in clinical trials have emerged, histone methylation modulations and the long non-coding RNA (lncRNA) are still under study. A comprehensive understanding of these other significant epigenetic modulations is still incomplete. This review aims to discuss some of the current studies on these two significant epigenetic modulations, histone methylation and lncRNA, as potential epigenetic targets in skeletal muscle regeneration. Understanding the mechanisms that initiate myoblast differentiation from its proliferative state to generate new muscle fibres will provide valuable information to advance the field of regenerative medicine and stem cell transplant.
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Affiliation(s)
- Magdaleena Naemi Mbadhi
- Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Jun-Ming Tang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Jing-Xuan Zhang
- Hubei Key Laboratory of Embryonic Stem Cell Research, Department of Physiology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
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Liu Y, Sun J, Qi P, Liu Y. Long non-coding RNA titin-antisense RNA1 contributes to growth and metastasis of cholangiocarcinoma by suppressing microRNA-513a-5p to upregulate stratifin. Bioengineered 2021; 12:12611-12624. [PMID: 34903127 PMCID: PMC8810091 DOI: 10.1080/21655979.2021.2011014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Cholangiocarcinoma (CCA) is one of the most common histological types of primary hepatic malignancy and is associated with poor overall prognosis, causing a ponderous burden on human life. Hence, it is necessary to elucidate the pathogenesis of CCA. The objective of our research was to shed light on the mechanism through which long non-coding RNA titin-antisense RNA1 (lncRNA TTN-AS1) is involved in the development of CCA. Reverse transcription quantitative polymerase chain reaction was used to detect TTN-AS1 expression in CCA samples and cells. Functional experiments were performed using the Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, transwell, and in vivo tumor growth assays. The relationship between TTN-AS1, miR-513a-5p, and stratifin (SFN) was explored using a dual luciferase reporter assay, RNA immunoprecipitation (RIP) experiment, and Pearson correlation analysis. The result showed that TTN-AS1 and SFN are highly expressed in CCA tissues. Bioinformatics analysis, luciferase reporter and RIP experiments revealed the correlation between TTN-AS1, miR-513a-5p, and SFN. In addition, silencing TTN-AS1 mitigated CCA cell proliferation and migration. Mechanistically, miR-513a-5p is sponged by TTN-AS1. The miR-513a-5p inhibitor abolished the effect of TTN-AS1 silencing on the aggressive behaviors of CCA cells. Furthermore, we showed that miR-513a-5p is a regulator of CCA by targeting SFN. TTN-AS1 induced CCA cell growth and metastasis via the miR-513a-5p/SFN pathway, which offers a new strategy for therapeutic interventions for CCA.
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Affiliation(s)
- Yang Liu
- Department of Hepatobiliary Surgery, Huanggang Center Hospital, Huanggang, Hubei, China
| | - Jiangyang Sun
- Department of Hepatobiliary Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Qi
- Department of General Surgery, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, Hubei, China
| | - Yang Liu
- Department of General Surgery, Hubei No. 3 People's Hospital of Jianghan University, Wuhan, Hubei, China
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Bonitto K, Sarathy K, Atai K, Mitra M, Coller HA. Is There a Histone Code for Cellular Quiescence? Front Cell Dev Biol 2021; 9:739780. [PMID: 34778253 PMCID: PMC8586460 DOI: 10.3389/fcell.2021.739780] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/17/2021] [Indexed: 12/14/2022] Open
Abstract
Many of the cells in our bodies are quiescent, that is, temporarily not dividing. Under certain physiological conditions such as during tissue repair and maintenance, quiescent cells receive the appropriate stimulus and are induced to enter the cell cycle. The ability of cells to successfully transition into and out of a quiescent state is crucial for many biological processes including wound healing, stem cell maintenance, and immunological responses. Across species and tissues, transcriptional, epigenetic, and chromosomal changes associated with the transition between proliferation and quiescence have been analyzed, and some consistent changes associated with quiescence have been identified. Histone modifications have been shown to play a role in chromatin packing and accessibility, nucleosome mobility, gene expression, and chromosome arrangement. In this review, we critically evaluate the role of different histone marks in these processes during quiescence entry and exit. We consider different model systems for quiescence, each of the most frequently monitored candidate histone marks, and the role of their writers, erasers and readers. We highlight data that support these marks contributing to the changes observed with quiescence. We specifically ask whether there is a quiescence histone “code,” a mechanism whereby the language encoded by specific combinations of histone marks is read and relayed downstream to modulate cell state and function. We conclude by highlighting emerging technologies that can be applied to gain greater insight into the role of a histone code for quiescence.
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Affiliation(s)
- Kenya Bonitto
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
| | - Kirthana Sarathy
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States
| | - Kaiser Atai
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States.,Molecular Biology Interdepartmental Doctoral Program, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Mithun Mitra
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Hilary A Coller
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States
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Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms222212280. [PMID: 34830163 PMCID: PMC8618067 DOI: 10.3390/ijms222212280] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 12/21/2022] Open
Abstract
Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer’s disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer’s disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.
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El-Khazragy N, Abdel Aziz MA, Hesham M, Matbouly S, Mostafa SA, Bakkar A, Abouelnile M, Noufal Y, Mahran NA, Abd Elkhalek MA, Abdelmaksoud MF. Upregulation of leukemia-induced non-coding activator RNA (LUNAR1) predicts poor outcome in pediatric T-acute lymphoblastic leukemia. Immunobiology 2021; 226:152149. [PMID: 34735923 DOI: 10.1016/j.imbio.2021.152149] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/12/2021] [Accepted: 10/16/2021] [Indexed: 12/20/2022]
Abstract
T-cell Acute Lymphoblastic Leukemia (T-ALL) accounts for around 10-15% of all lymphoblastic leukemia in children. Previous studies have proven that dysregulation of Leukemia-induced non-coding activator RNA-1 (LUNAR1) expression promotes T-ALL cell growth by enhancing the NOTCH1/IGF-1R signaling pathway. We aimed to investigate the prognostic value of LUNAR1 in pediatric T-ALL, in addition, to find out its association with NOTCH1 and IGF-1R. The LUNAR1, NOTCH1, and IGF-IR gene expression were measured in peripheral blood (PB) samples of l85 children with T-ALL and forty non-leukemic samples as a control group. Cox regression analysis revealed that overexpression of LUNAR1, NOTCH1, and IGF-IR was significantly correlated with poor prognosis, short overall survival, and progression-free survival. We concluded that LUNAR1 could serve as an independent prognostic biomarker for T-ALL in children.
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Affiliation(s)
- Nashwa El-Khazragy
- Department of Clinical Pathology-Hematology and Ain Shams Medical Research Institute (MASRI), Faculty of Medicine, Ain Shams University, Cairo, Egypt.
| | | | - Manar Hesham
- Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
| | - Safa Matbouly
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sally Abdallah Mostafa
- Medical Biochemistry Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ashraf Bakkar
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt
| | - Mariam Abouelnile
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt
| | - Yassmin Noufal
- Faculty of Biotechnology, October University for Modern Sciences and Arts, Giza, Egypt
| | - Nievin Ahmed Mahran
- Biochemistry Department, Faculty of Dentistry, Sinai University, Kanatra, Egypt
| | - Marwa Ali Abd Elkhalek
- Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Saliani M, Mirzaiebadizi A, Mosaddeghzadeh N, Ahmadian MR. RHO GTPase-Related Long Noncoding RNAs in Human Cancers. Cancers (Basel) 2021; 13:5386. [PMID: 34771549 PMCID: PMC8582479 DOI: 10.3390/cancers13215386] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/27/2022] Open
Abstract
RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis.
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Affiliation(s)
- Mahsa Saliani
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
| | - Amin Mirzaiebadizi
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Niloufar Mosaddeghzadeh
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Mohammad Reza Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
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Rodriguez FD. Targeting Epigenetic Mechanisms to Treat Alcohol Use Disorders (AUD). Curr Pharm Des 2021; 27:3252-3272. [PMID: 33535943 PMCID: PMC8778698 DOI: 10.2174/1381612827666210203142539] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/08/2020] [Indexed: 12/04/2022]
Abstract
BACKGROUND The impact of abusive alcohol consumption on human health is remarkable. According to the World Health Organization (WHO), approximately 3.3 million people die annually because of harmful alcohol consumption (the figure represents around 5.9% of global deaths). Alcohol Use Disorder (AUD) is a chronic disease where individuals exhibit compulsive alcohol drinking and present negative emotional states when they do not drink. In the most severe manifestations of AUD, the individuals lose control over intake despite a decided will to stop drinking. Given the multiple faces and the specific forms of this disease, the term AUD often appears in the plural (AUDs). Since only a few approved pharmacological treatments are available to treat AUD and they do not apply to all individuals or AUD forms, the search for compounds that may help to eliminate the burden of the disease and complement other therapeutical approaches is necessary. METHODS This work reviews recent research focused on the involvement of epigenetic mechanisms in the pathophysiology of AUD. Excessive drinking leads to chronic and compulsive consumption that eventually damages the organism. The central nervous system is a key target and is the focus of this study. The search for the genetic and epigenetic mechanisms behind the intricated dysregulation induced by ethanol will aid researchers in establishing new therapy approaches. CONCLUSION Recent findings in the field of epigenetics are essential and offer new windows for observation and research. The study of small molecules that inhibit key epienzymes involved in nucleosome architecture dynamics is necessary in order to prove their action and specificity in the laboratory and to test their effectivity and safety in clinical trials with selected patients bearing defined alterations caused by ethanol.
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Affiliation(s)
- F. David Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca and Group GIR BMD (Bases Moleculares del Desarrollo), University of Salamanca, Salamanca, Spain
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Dey P, Mattick JS. High frequency of intron retention and clustered H3K4me3-marked nucleosomes in short first introns of human long non-coding RNAs. Epigenetics Chromatin 2021; 14:45. [PMID: 34579770 PMCID: PMC8477579 DOI: 10.1186/s13072-021-00419-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/27/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND It is established that protein-coding exons are preferentially localized in nucleosomes. To examine whether the same is true for non-coding exons, we analysed nucleosome occupancy in and adjacent to internal exons in genes encoding long non-coding RNAs (lncRNAs) in human CD4+ T cells and K562 cells. RESULTS We confirmed that internal exons in lncRNAs are preferentially associated with nucleosomes, but also observed an elevated signal from H3K4me3-marked nucleosomes in the sequences upstream of these exons. Examination of 200 genomic lncRNA loci chosen at random across all chromosomes showed that high-density regions of H3K4me3-marked nucleosomes, which we term 'slabs', are associated with genomic regions exhibiting intron retention. These retained introns occur in over 50% of lncRNAs examined and are mostly first introns with an average length of just 354 bp, compared to the average length of all human introns of 6355 and 7987 bp in mRNAs and lncRNAs, respectively. Removal of short introns from the dataset abrogated the high upstream H3K4me3 signal, confirming that the association of slabs and short lncRNA introns with intron retention holds genome-wide. The high upstream H3K4me3 signal is also associated with alternatively spliced exons, known to be prominent in lncRNAs. This phenomenon was not observed with mRNAs. CONCLUSIONS There is widespread intron retention and clustered H3K4me3-marked nucleosomes in short first introns of human long non-coding RNAs, which raises intriguing questions about the relationship of IR to lncRNA function and chromatin organization.
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Affiliation(s)
- Pinki Dey
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, 2052, Sydney, Australia
| | - John S Mattick
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, 2052, Sydney, Australia.
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Masoumi F, Saraiva SM, Bouzo BL, López-López R, Esteller M, Díaz-Lagares Á, de la Fuente M. Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem. Pharmaceutics 2021; 13:pharmaceutics13091507. [PMID: 34575588 PMCID: PMC8470159 DOI: 10.3390/pharmaceutics13091507] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/06/2021] [Accepted: 09/14/2021] [Indexed: 01/01/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are an emerging group of RNAs with a crucial role in cancer pathogenesis. In gastrointestinal cancers, TP53 target 1 (TP53TG1) is an epigenetically regulated lncRNA that represents a promising therapeutic target due to its tumor suppressor properties regulating the p53-mediated DNA damage and the intracellular localization of the oncogenic YBX1 protein. However, to translate this finding into the clinic as a gene therapy, it is important to develop effective carriers able to deliver exogenous lncRNAs to the targeted cancer cells. Here, we propose the use of biocompatible sphingomyelin nanosystems comprising DOTAP (DSNs) to carry and deliver a plasmid vector encoding for TP53TG1 (pc(TP53TG1)-DSNs) to a colorectal cancer cell line (HCT-116). DSNs presented a high association capacity and convenient physicochemical properties. In addition, pc(TP53TG1)-DSNs showed anti-tumor activities in vitro, specifically a decrease in the proliferation rate, a diminished colony-forming capacity, and hampered migration and invasiveness of the treated cancer cells. Consequently, the proposed strategy displays a high potential as a therapeutic approach for colorectal cancer.
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Affiliation(s)
- Farimah Masoumi
- Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (F.M.); (S.M.S.); (B.L.B.)
- Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran 14176-13151, Iran
- School of Medicine, Tonekabon Branch, Islamic Azad University, Tonekabon 46841-61167, Iran
| | - Sofia M. Saraiva
- Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (F.M.); (S.M.S.); (B.L.B.)
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain; (R.L.-L.); (M.E.)
| | - Belén L. Bouzo
- Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (F.M.); (S.M.S.); (B.L.B.)
| | - Rafael López-López
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain; (R.L.-L.); (M.E.)
- Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain
| | - Manel Esteller
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain; (R.L.-L.); (M.E.)
- Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain
- Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08907 Barcelona, Spain
- Institucio Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Ángel Díaz-Lagares
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain; (R.L.-L.); (M.E.)
- Cancer Epigenomics, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago (CHUS), SERGAS, 15706 Santiago de Compostela, Spain
- Correspondence: (A.D.-L.); (M.d.l.F.)
| | - María de la Fuente
- Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, 15706 Santiago de Compostela, Spain; (F.M.); (S.M.S.); (B.L.B.)
- Centro de Investigación Biomédica en Red de Cancer (CIBERONC), 28029 Madrid, Spain; (R.L.-L.); (M.E.)
- Correspondence: (A.D.-L.); (M.d.l.F.)
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