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1
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Fang J, Zou M, Yang M, Cui Y, Pu R, Yang Y. TAF15 inhibits p53 nucleus translocation and promotes HCC cell 5-FU resistance via post-transcriptional regulation of UBE2N. J Physiol Biochem 2024; 80:919-933. [PMID: 39446246 DOI: 10.1007/s13105-024-01053-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024]
Abstract
Chemotherapy resistance is an important factor responsible for the low 5-year survival rate of hepatocellular carcinoma (HCC) patients. Ubiquitin-conjugating enzyme E2N (UBE2N) is a cancer-associated ubiquitin-conjugating enzyme that is expressed in HCC tissues, and its high expression is associated with a poor prognosis. This study explored the role played by UBE2N in development of 5-fluorouracil (5-FU) resistance in HCC cells. Three HCC cell lines (HepG2 [p53 wild type], Huh7 [p53 point mutant type], Hep3B [p53 non-expression type]), and one normal liver cell line (MIHA) were used in our present study. The IC50 value of 5-FU was determined using a cell counting kit-8 (CCK-8) assay. Cell viability was assessed by colony formation assays. TUNEL assays and flow cytometry were used to analyze cell apoptosis. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to confirm the binding relationship between UBE2N mRNA and TAF15 protein. Our results showed that TAF15 and UBE2N were highly expressed in HCC cells. UBE2N inhibited the translocation of p53 protein into the cell nucleus to increase 5-FU resistance, as reflected by an increased IC50 value, an increase in cell viability, and a reduction in cell apoptosis. Overexpression of p53 reduced 5-FU resistance, but that effect could be reversed by UBE2N overexpression. TAF15 protein bound to and stabilized UBE2N mRNA, thereby inhibiting p53 translocation into the nucleus and promoting 5-FU resistance in HCC cells. Collectively, our present study identified a novel mechanism by which TAF15/UBE2N regulates p53 distribution to increase 5-FU resistance. Our results also suggest potential therapeutic strategies for treating HCC.
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Affiliation(s)
- Jiayan Fang
- Department of Internal Medicine-Oncology, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, 523326, China
| | - Mengqi Zou
- Department of Pathology, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Xianglong Road of Shilong Town, Dongguan, 523326, China
| | - Mei Yang
- Department of Internal Medicine-Oncology, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, 523326, China
| | - Yejia Cui
- Department of Laboratory, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, 523326, China
| | - Rong Pu
- Department of Laboratory, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, 523326, China
| | - Yufeng Yang
- Department of Pathology, The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, No.1, Xianglong Road of Shilong Town, Dongguan, 523326, China.
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Elpek GO. Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors. World J Gastroenterol 2024; 30:3367-3372. [PMID: 39091718 PMCID: PMC11290397 DOI: 10.3748/wjg.v30.i28.3367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 06/19/2024] [Accepted: 07/02/2024] [Indexed: 07/24/2024] Open
Abstract
In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Türkiye
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3
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Luna-Arias JP, Castro-Muñozledo F. Participation of the TBP-associated factors (TAFs) in cell differentiation. J Cell Physiol 2024; 239:e31167. [PMID: 38126142 DOI: 10.1002/jcp.31167] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/04/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023]
Abstract
The understanding of the mechanisms that regulate gene expression to establish differentiation programs and determine cell lineages, is one of the major challenges in Developmental Biology. Besides the participation of tissue-specific transcription factors and epigenetic processes, the role of general transcription factors has been ignored. Only in recent years, there have been scarce studies that address this issue. Here, we review the studies on the biological activity of some TATA-box binding protein (TBP)-associated factors (TAFs) during the proliferation of stem/progenitor cells and their involvement in cell differentiation. Particularly, the accumulated evidence suggests that TAF4, TAF4b, TAF7L, TAF8, TAF9, and TAF10, among others, participate in nervous system development, adipogenesis, myogenesis, and epidermal differentiation; while TAF1, TAF7, TAF15 may be involved in the regulation of stem cell proliferative abilities and cell cycle progression. On the other hand, evidence suggests that TBP variants such as TBPL1 and TBPL2 might be regulating some developmental processes such as germ cell maturation and differentiation, myogenesis, or ventral specification during development. Our analysis shows that it is necessary to study in greater depth the biological function of these factors and its participation in the assembly of specific transcription complexes that contribute to the differential gene expression that gives rise to the great diversity of cell types existing in an organism. The understanding of TAFs' regulation might lead to the development of new therapies for patients which suffer from mutations, alterations, and dysregulation of these essential elements of the transcriptional machinery.
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Affiliation(s)
- Juan Pedro Luna-Arias
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México City, Mexico
| | - Federico Castro-Muñozledo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México City, Mexico
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Zheng WH, Long ZQ, Zheng ZQ, Zhang LL, Liang YL, Li ZX, Lv JW, Kou J, Hong XH, He SW, Xu R, Zhou GQ, Liu N, Ma J, Sun Y, Lin L, Wei D. m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma. J Biol Chem 2023:104873. [PMID: 37257820 PMCID: PMC10302167 DOI: 10.1016/j.jbc.2023.104873] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 05/15/2023] [Accepted: 05/16/2023] [Indexed: 06/02/2023] Open
Abstract
Dysregulation of long non-coding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of m6A-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues, as well as in 10 paired samples from NPC with or without posttreatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pulldown assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, ChIP and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis, and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.
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Affiliation(s)
- Wei-Hong Zheng
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Zhi-Qing Long
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Zi-Qi Zheng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Lu-Lu Zhang
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China
| | - Ye-Lin Liang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Zhi-Xuan Li
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Jia-Wei Lv
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China
| | - Jia Kou
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China
| | - Xiao-Hong Hong
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Shi-Wei He
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Rui Xu
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Guan-Qun Zhou
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China
| | - Na Liu
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Jun Ma
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Ying Sun
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China; State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Li Lin
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, People's Republic of China.
| | - Denghui Wei
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center.
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Guo CM, Tang L, Li X, Huang LY. TATA-box-binding protein-associated factor 15 is a novel biomarker that promotes cell proliferation and migration in gastrointestinal stromal tumor. World J Gastroenterol 2023; 29:2932-2949. [PMID: 37274797 PMCID: PMC10237090 DOI: 10.3748/wjg.v29.i19.2932] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/06/2023] [Accepted: 04/11/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) is a common neoplasm with high rates of recurrence and metastasis, and its therapeutic efficacy is still not ideal. There is an unmet need to find new molecular therapeutic targets for GIST. TATA-box-binding protein-associated factor 15 (TAF15) contributes to the progress of various tumors, while the role and molecular mechanism of TAF15 in GIST progression are still unknown.
AIM To explore new molecular therapeutic targets for GIST and understand the biological role and underlying mechanisms of TAF15 in GIST progression.
METHODS Proteomic analysis was performed to explore the differentially expressed proteins in GIST. Western blotting and immunohistochemical analysis were used to verify the expression level of TAF15 in GIST tissues and cell lines. Cell counting kit-8, colony formation, wound-healing and transwell assay were executed to detect the ability of TAF15 on cell proliferation, migration and invasion. A xenograft mouse model was applied to explore the role of TAF15 in the progression of GIST. Western blotting was used to detect the phosphorylation level and total level of RAF1, MEK and ERK1/2.
RESULTS A total of 1669 proteins were identified as differentially expressed proteins with 762 upregulated and 907 downregulated in GIST. TAF15 was selected for the further study because of its important role in cell proliferation and migration. TAF15 was significantly over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with larger tumor size and higher risk stage of GIST. TAF15 knockdown significantly inhibited the cell proliferation and migration of GIST in vitro and suppressed tumor growth in vivo. Moreover, the inhibition of TAF15 expression significantly decreased the phosphorylation level of RAF1, MEK and ERK1/2 in GIST cells and xenograft tissues, while the total RAF1, MEK and ERK1/2 had no significant change.
CONCLUSION TAF15 is over expressed in GIST tissues and cell lines. Overexpression of TAF15 was associated with a poor prognosis of GIST patients. TAF15 promotes cell proliferation and migration in GIST via the activation of the RAF1/MEK/ERK signaling pathway. Thus, TAF15 is expected to be a novel latent molecular biomarker or therapeutic target of GIST.
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Affiliation(s)
- Cheng-Ming Guo
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China
| | - Li Tang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China
| | - Xu Li
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China
| | - Liu-Ye Huang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai 264000, Shandong Province, China
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6
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Tang L, Guo C, Li X, Zhang B, Huang L. TAF15 promotes cell proliferation, migration and invasion of gastric cancer via activation of the RAF1/MEK/ERK signalling pathway. Sci Rep 2023; 13:5846. [PMID: 37037864 PMCID: PMC10086039 DOI: 10.1038/s41598-023-31959-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/20/2023] [Indexed: 04/12/2023] Open
Abstract
TATA-box-binding protein-associated Factor 15 (TAF15), a member of the FUS/EWS/TAF15 (FET) family, contributes to the progression of various tumours. However, the role and molecular mechanism of TAF15 in gastric cancer (GC) progression are still unknown. In this study, we found that TAF15 was significantly upregulated in GC tumour tissues and cell lines. Overexpression of TAF15 was associated with a larger tumour size, high pathologic stage and high T stage of GC. TAF15 knockdown suppressed the proliferation, migration and invasion of GC cells in vitro and inhibited the tumour growth in vivo. Additionally, TAF15 knockdown led to the significant reductions in the phosphorylation levels of RAF1, MEK and ERK1/2, while total RAF1, MEK and ERK1/2 exhibited no significant change in GC cell lines. In summary, TAF15 is overexpressed in GC tumour tissues and cell lines, and promotes cell proliferation, migration and invasion in GC via the RAF1/MEK/ERK signaling pathway, which suggests that TAF15 might be a potential molecular diagnostic marker or therapeutic target for GC.
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Affiliation(s)
- Li Tang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, People's Republic of China
| | - Chengming Guo
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, People's Republic of China
| | - Xu Li
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, People's Republic of China
| | - Bo Zhang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, People's Republic of China
| | - Liuye Huang
- Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, People's Republic of China.
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Secchi M, Lodola C, Garbelli A, Bione S, Maga G. DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective. Cancers (Basel) 2022; 14:cancers14153820. [PMID: 35954483 PMCID: PMC9367324 DOI: 10.3390/cancers14153820] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/01/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The transformation of a normal cell into a cancerous one is caused by the deregulation of different metabolic pathways, involving a complex network of protein–protein interactions. The cellular enzymes DDX3X and DDX5 play important roles in the maintenance of normal cell metabolism, but their deregulation can accelerate tumor transformation. Both DDX3X and DDX5 interact with hundreds of different cellular proteins, and depending on the specific pathways in which they are involved, both proteins can either act as suppressors of cancer or as oncogenes. In this review, we summarize the current knowledge about the roles of DDX3X and DDX5 in different tumors. In addition, we present a list of interacting proteins and discuss the possible contribution of some of these protein–protein interactions in determining the roles of DDX3X and DDX5 in the process of cancer proliferation, also suggesting novel hypotheses for future studies. Abstract RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.
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Wang M, Xu T, Feng W, Liu J, Wang Z. Advances in Understanding the LncRNA-Mediated Regulation of the Hippo Pathway in Cancer. Onco Targets Ther 2021; 14:2397-2415. [PMID: 33854336 PMCID: PMC8039192 DOI: 10.2147/ott.s283157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 03/08/2021] [Indexed: 12/24/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and cannot encode proteins. Over the past decade, lncRNAs have been defined as regulatory elements of multiple biological processes, and their aberrant expression contributes to the development and progression of various malignancies. Recent studies have shown that lncRNAs are involved in key cancer-related signaling pathways, including the Hippo signaling pathway, which plays a prominent role in controlling organ size and tissue homeostasis by regulating cell proliferation, apoptosis, and differentiation. However, dysregulation of this pathway is associated with pathological conditions, especially cancer. Accumulating evidence has revealed that lncRNAs can modulate the Hippo signaling pathway in cancer. In this review, we elaborate on the role of the Hippo signaling pathway and the advances in the understanding of its lncRNA-mediated regulation in cancer. This review provides additional insight into carcinogenesis and will be of great clinical value for developing novel early detection and treatment strategies for this deadly disease.
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Affiliation(s)
- Mengwei Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Tianwei Xu
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Wenyan Feng
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Junxia Liu
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Zhaoxia Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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Ren P, Xing L, Hong X, Chang L, Zhang H. LncRNA PITPNA-AS1 boosts the proliferation and migration of lung squamous cell carcinoma cells by recruiting TAF15 to stabilize HMGB3 mRNA. Cancer Med 2020; 9:7706-7716. [PMID: 32871048 PMCID: PMC7571819 DOI: 10.1002/cam4.3268] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/25/2020] [Accepted: 06/02/2020] [Indexed: 12/21/2022] Open
Abstract
Plenty of reports have probed the involvement of abnormally expressed lncRNAs in multiple cancers, including lung squamous cell carcinoma (LUSC). Through online database GEPIA, lncRNA PITPNA antisense RNA 1 (PITPNA-AS1) was highly expressed in LUSC samples, and these tendency was further affirmed in LUSC cells. The aim of current study was to investigate the related mechanism of PITPNA-AS1 in LUSC. Functional experiments verified that depletion of PITPNA-AS1 hampered the proliferative and migratory abilities, but accelerated apoptosis of LUSC cells. Additionally, we observed the increased expression of HMGB3 and its positive correlation with PITPNA-AS1 in LUSC samples. Interestingly, PITPNA-AS1 mainly located in the cytosol of LUSC cells, and also affected mRNA stability of HMGB3. Furthermore, the repressed mRNA stability of HMGB3 by PITPNA-AS1 via TAF15 was exposed through mechanism experiments. The mediatory function of PITPNA-AS1 on HMGB3 was validated via rescue assays. All in all, PITPNA-AS1 promoted the proliferation and migration of LUSC cells via stabilizing HMGB3 by TAF15. In conclusion, our study displayed a novel mechanism underlying PITPNA-AS1 in LUSC cells.
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Affiliation(s)
- Ping Ren
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Lei Xing
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Xiaodong Hong
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Liang Chang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
| | - Hong Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, P.R. China
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10
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Singh AK, Kapoor V, Thotala D, Hallahan DE. TAF15 contributes to the radiation-inducible stress response in cancer. Oncotarget 2020; 11:2647-2659. [PMID: 32676166 PMCID: PMC7343639 DOI: 10.18632/oncotarget.27663] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/15/2020] [Indexed: 12/28/2022] Open
Abstract
Resistance to radiation therapy is a significant problem in the treatment of non-small cell lung cancer (NSCLC). There is an unmet need to discover new molecular targets for drug development in combination with standard of care cancer therapy. We found that TAF15 was radiation-inducible using phage-displayed peptide libraries. In this study, we report that overexpression of TAF15 is correlated with worsened survival in NSCLC patients. Radiation treatment led to surface induction of TAF15 in vitro and in vivo. We genetically silenced TAF15 which led to a significant reduction in proliferation of NSCLC cells. Cells depleted of TAF15 exhibited cell cycle arrest and enhanced apoptosis through activation and accumulation of p53. In combination with radiation, TAF15 knockdown led to a significant reduction in the surviving fraction of NSCLC cell lines. To determine the importance of TAF15 surface expression, we targeted TAF15 with an antibody. In combination with radiation, the anti-TAF15 antibody led to a reduction in the surviving fraction of cancer cells. These studies show that TAF15 is a radiation-inducible molecular target that is accessible to anti-cancer antibodies and enhances cell viability in response to radiation.
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Affiliation(s)
- Abhay Kumar Singh
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Vaishali Kapoor
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Dinesh Thotala
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.,Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Dennis E Hallahan
- Department of Radiation Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.,Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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11
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Ruan X, Zheng J, Liu X, Liu Y, Liu L, Ma J, He Q, Yang C, Wang D, Cai H, Li Z, Liu J, Xue Y. lncRNA LINC00665 Stabilized by TAF15 Impeded the Malignant Biological Behaviors of Glioma Cells via STAU1-Mediated mRNA Degradation. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 20:823-840. [PMID: 32464546 PMCID: PMC7256440 DOI: 10.1016/j.omtn.2020.05.003] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/23/2020] [Accepted: 05/01/2020] [Indexed: 12/11/2022]
Abstract
Glioma is a brain cancer characterized by strong invasiveness with limited treatment options and poor prognosis. Recently, dysregulation of long non-coding RNAs (lncRNAs) has emerged as an important component in cellular processes and tumorigenesis. In this study, we demonstrated that TATA-box binding protein associated factor 15 (TAF15) and long intergenic non-protein coding RNA 665 (LINC00665) were both downregulated in glioma tissues and cells. TAF15 overexpression enhanced the stability of LINC00665, inhibiting malignant biological behaviors of glioma cells. Both metal regulatory transcription factor 1 (MTF1) and YY2 transcription factor (YY2) showed high expression levels in glioma tissues and cells, and their knockdown inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNA by interacting with STAU1, and knockdown of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. G2 and S-phase expressed 1 (GTSE1) was identified as an oncogene in glioma, and knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to the GTSE1 promoter region. Our study highlights a key role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in modulating the malignant biological behaviors of glioma cells, suggesting novel mechanisms by which lncRNAs affect STAU1-mediated mRNA stability, which can inform new molecular therapies for glioma.
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Affiliation(s)
- Xuelei Ruan
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Jian Zheng
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Xiaobai Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Yunhui Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Libo Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Jun Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Qianru He
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China
| | - Chunqing Yang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Di Wang
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Heng Cai
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Zhen Li
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Jing Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China
| | - Yixue Xue
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China.
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USF1-induced upregulation of LINC01048 promotes cell proliferation and apoptosis in cutaneous squamous cell carcinoma by binding to TAF15 to transcriptionally activate YAP1. Cell Death Dis 2019; 10:296. [PMID: 30931936 PMCID: PMC6443651 DOI: 10.1038/s41419-019-1516-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/18/2019] [Accepted: 03/06/2019] [Indexed: 02/07/2023]
Abstract
Previous studies have revealed that dysregulation of long non-coding RNAs (lncRNAs) can facilitate carcinogenesis. This study aims to investigate the biological role of a certain lncRNA in cutaneous squamous cell carcinoma (CSCC). According to the data of TCGA database, high expression of long intergenic non-protein coding RNA 1048 (LINC01048) is an unfavorable prognostic factor for patients with CSCC. Therefore, we further detected the expression pattern of LINC01048 in CSCC tissues. Obviously, LINC01048 was expressed higher in the CSCC tissues and recurrence tissues compared with that in adjacent normal tissues and non-recurrence tissues. Furthermore, Kaplan-Meier analysis revealed the negative correlation between LINC01048 expression and the overall survival and disease-free survival of CSCC patients. Subsequently, functional assays were conducted to prove the inhibitory effect of silenced LINC01048 on the proliferation and apoptosis of CSCC cells. Mechanistically, LINC01048 was proved to be transcriptionally activated by USF1. Pathway analysis and western blot assay showed that knockdown of LINC01048 led to the activation of Hippo pathway. Moreover, YAP1, a Hippo pathway factor, was positively regulated by LINC01048. Further mechanism investigation revealed that LINC01048 increased the binding of TAF15 to YAP1 promoter to transcriptionally activate YAP1 in CSCC cells. Finally, rescue assays demonstrated that YAP1 involved in LINC01048-mediated CSCC cell proliferation and apoptosis. In conclusion, USF1-induced upregulation of LINC01048 promoted CSCC by interacting with TAF15 to upregulate YAP1.
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Kume K, Ikeda M, Miura S, Ito K, Sato KA, Ohmori Y, Endo F, Katagiri H, Ishida K, Ito C, Iwaya T, Nishizuka SS. α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15. Sci Rep 2016; 6:25895. [PMID: 27181033 PMCID: PMC4867652 DOI: 10.1038/srep25895] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 04/25/2016] [Indexed: 12/30/2022] Open
Abstract
Cancer relapse occurs with substantial frequency even after treatment with curative intent. Here we studied drug-tolerant colonies (DTCs), which are subpopulations of cancer cells that survive in the presence of drugs. Proteomic characterization of DTCs identified stemness- and epithelial-dominant subpopulations, but functional screening suggested that DTC formation was regulated at the transcriptional level independent from protein expression patterns. We consistently found that α-amanitin, an RNA polymerase II (RNAPII) inhibitor, effectively inhibited DTCs by suppressing TAF15 expression, which binds to RNA to modulate transcription and RNA processing. Sequential administration of α-amanitin and cisplatin extended overall survival in a cancer-relapse mouse model, namely peritonitis carcinomatosa. Therefore, post-treatment cancer relapse may occur through non-distinct subpopulations and may be effectively prevented by α-amanitin to disrupt transcriptional machinery, including TAF15.
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Affiliation(s)
- Kohei Kume
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.,MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.,Institute of Biomedical Science, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
| | - Miyuki Ikeda
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Sawako Miura
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kohei Ito
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kei A Sato
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Yukimi Ohmori
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.,MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Fumitaka Endo
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Hirokatsu Katagiri
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Kaoru Ishida
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Chie Ito
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Takeshi Iwaya
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan
| | - Satoshi S Nishizuka
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.,MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University School of Medicine, Morioka, Iwate 020-8505, Japan.,Institute of Biomedical Science, Iwate Medical University, Yahaba, Iwate 028-3694, Japan
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Grammatico S, Vitale A, La Starza R, Gorello P, Angelosanto N, Negulici AD, De Propris MS, Nanni M, Meloni G, Mecucci C, Foà R. Lineage switch from pro-B acute lymphoid leukemia to acute myeloid leukemia in a case with t(12;17)(p13;q11)/TAF15–ZNF384rearrangement. Leuk Lymphoma 2013. [DOI: 10.3109/10428194.2012.753450] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Schwartz-Albiez R. Naturally occurring antibodies directed against carbohydrate tumor antigens. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 750:27-43. [PMID: 22903664 DOI: 10.1007/978-1-4614-3461-0_3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Healthy persons carry within their pool of circulating antibodies immunoglobulins preferentially of IgM isotype, which are directed against a variety of tumor-associated antigens. In closer scrutiny of their nature, some of these antibodies could be defined as naturally occurring antibodies due to the germline configuration of the variable immunoglobulin region. The majority of these immunoglobulins recognize carbohydrate antigens which can be classified as oncofetal antigens. Many of these IgM antibodies present in the peripheral blood circulation can bind to tumor cells and of these a minor portion are also able to destroy tumor cells by several mechanisms, as for instance complement-mediated cytolysis or apoptosis. It was postulated that anti-carbohydrate antibodies are part of an anti-tumor immune response, while their presence in the peripheral blood of healthy donors is still waiting for a plausible explanation. It may be that recognition of defined epitopes, including carbohydrate sequences, by naturally occurring antibodies constitutes the humoral arm of an anti-tumor immune response as part of the often postulated tumor surveillance. The cytotoxic capacity of these antibodies inspired several research groups and pharmaceutical companies to design novel strategies of immunoglobulin-based anti-tumor immunotherapy.
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