CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer

• Published in: Clinical and translational medicine Vol. 12; no. 10; pp. e1087 - n/a
• Main Authors: Dai, Wei, Wu, Junhong, Peng, Xiaopeng, Hou, Wen, Huang, Hao, Cheng, Qilai, Liu, Zhiping, Luyten, Walter, Schoofs, Liliane, Zhou, Jingfeng, Liu, Shenglan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.10.2022; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Bone cancer; Carcinogenesis - genetics; CCDC137; CDK12; Cell Proliferation - genetics; Clinical medicine; Cloning; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CRISPR; Cyclin-dependent kinases; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; DNA damage; Epigenetics; Ewings sarcoma; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Humans; Kinases; Liver; liver metastasis; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - secondary; Metastasis; Polymerase chain reaction; RNA polymerase; super‐enhancers; United States > US; China; liver metastasis; colorectal cancer; CDK12; CCDC137; super-enhancers
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1087

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. Super‐enhancers fostered metastasis‐related cellular features (proliferation, survival, stemness) in CRC cells via driving overexpression of super enhancer‐associate genes BCL2L1 and CCDC137. Disruption of SEs by CDK12 inhibition with SR4835 or shRNA lentivirus efficiently eliminated liver metastasis through downregulating transcription of relevant genes. CCDC137 promotes proliferation and cancer stem‐like cells in CRC.