CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer
Abstract Background Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. Methods Th...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.1087 |
| _version_ | 1817976121703006208 |
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| author | Wei Dai Junhong Wu Xiaopeng Peng Wen Hou Hao Huang Qilai Cheng Zhiping Liu Walter Luyten Liliane Schoofs Jingfeng Zhou Shenglan Liu |
| author_facet | Wei Dai Junhong Wu Xiaopeng Peng Wen Hou Hao Huang Qilai Cheng Zhiping Liu Walter Luyten Liliane Schoofs Jingfeng Zhou Shenglan Liu |
| author_sort | Wei Dai |
| collection | DOAJ |
| description | Abstract Background Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. Methods The transcriptional profiles of super‐enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR‐4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. Results We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE‐associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE‐associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. Conclusions Our data highlight the potential of CDK12 and SE‐associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC. |
| first_indexed | 2024-04-13T21:58:16Z |
| format | Article |
| id | doaj.art-6c5cfe2e07204a19b6cd377fbda17070 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-13T21:58:16Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj.art-6c5cfe2e07204a19b6cd377fbda170702022-12-22T02:28:10ZengWileyClinical and Translational Medicine2001-13262022-10-011210n/an/a10.1002/ctm2.1087CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancerWei Dai0Junhong Wu1Xiaopeng Peng2Wen Hou3Hao Huang4Qilai Cheng5Zhiping Liu6Walter Luyten7Liliane Schoofs8Jingfeng Zhou9Shenglan Liu10School of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaCenter for Immunology Gannan Medical University Ganzhou Jiangxi ChinaDepartment of Biology KU Leuven Leuven BelgiumDepartment of Biology KU Leuven Leuven BelgiumDepartment of Hematology and Oncology International Cancer Center Shenzhen Key Laboratory Shenzhen University General Hospital Shenzhen University Clinical Medical Academy Shenzhen University Health Science Center Shenzhen ChinaSchool of Pharmacy Gannan Medical University Ganzhou Jiangxi ChinaAbstract Background Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. Methods The transcriptional profiles of super‐enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR‐4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. Results We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE‐associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE‐associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. Conclusions Our data highlight the potential of CDK12 and SE‐associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.https://doi.org/10.1002/ctm2.1087CCDC137CDK12colorectal cancerliver metastasissuper‐enhancers |
| spellingShingle | Wei Dai Junhong Wu Xiaopeng Peng Wen Hou Hao Huang Qilai Cheng Zhiping Liu Walter Luyten Liliane Schoofs Jingfeng Zhou Shenglan Liu CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer Clinical and Translational Medicine CCDC137 CDK12 colorectal cancer liver metastasis super‐enhancers |
| title | CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer |
| title_full | CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer |
| title_fullStr | CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer |
| title_full_unstemmed | CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer |
| title_short | CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer |
| title_sort | cdk12 orchestrates super enhancer associated ccdc137 transcription to direct hepatic metastasis in colorectal cancer |
| topic | CCDC137 CDK12 colorectal cancer liver metastasis super‐enhancers |
| url | https://doi.org/10.1002/ctm2.1087 |
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