Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities
Abstract Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05736-w |
| _version_ | 1797849834858741760 |
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| author | Li-Ting Shen Lin-Rong Che Zongsheng He Qian Lu Dong-Feng Chen Zhong-yi Qin Bin Wang |
| author_facet | Li-Ting Shen Lin-Rong Che Zongsheng He Qian Lu Dong-Feng Chen Zhong-yi Qin Bin Wang |
| author_sort | Li-Ting Shen |
| collection | DOAJ |
| description | Abstract Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics. In this review, we discuss advances in our understanding of m6A RNA modification since its discovery in the 1970s to the latest progress in defining its potential clinic relevance. We summarize the molecular basis and roles of m6A regulators in the hallmarks of GI cancer and discuss their context-dependent functions. Furthermore, the identification and characterization of inhibitors or activators of m6A regulators and their potential anti-cancer effects are discussed. With the rapid growth in this field there is significant potential for developing m6A targeted therapy in GI cancers. |
| first_indexed | 2024-04-09T18:50:36Z |
| format | Article |
| id | doaj.art-6900d05c344c4269a013d88edc03ca7a |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-09T18:50:36Z |
| publishDate | 2023-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6900d05c344c4269a013d88edc03ca7a2023-04-09T11:28:18ZengNature Publishing GroupCell Death and Disease2041-48892023-04-0114411710.1038/s41419-023-05736-wAberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunitiesLi-Ting Shen0Lin-Rong Che1Zongsheng He2Qian Lu3Dong-Feng Chen4Zhong-yi Qin5Bin Wang6Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Department of Gastroenterology & Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)Abstract Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics. In this review, we discuss advances in our understanding of m6A RNA modification since its discovery in the 1970s to the latest progress in defining its potential clinic relevance. We summarize the molecular basis and roles of m6A regulators in the hallmarks of GI cancer and discuss their context-dependent functions. Furthermore, the identification and characterization of inhibitors or activators of m6A regulators and their potential anti-cancer effects are discussed. With the rapid growth in this field there is significant potential for developing m6A targeted therapy in GI cancers.https://doi.org/10.1038/s41419-023-05736-w |
| spellingShingle | Li-Ting Shen Lin-Rong Che Zongsheng He Qian Lu Dong-Feng Chen Zhong-yi Qin Bin Wang Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities Cell Death and Disease |
| title | Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| title_full | Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| title_fullStr | Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| title_full_unstemmed | Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| title_short | Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| title_sort | aberrant rna m6a modification in gastrointestinal malignancies versatile regulators of cancer hallmarks and novel therapeutic opportunities |
| url | https://doi.org/10.1038/s41419-023-05736-w |
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