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 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.

Cyclin‐dependent kinase 12‐mediated super‐enhancers as promising targets in cancer therapy

“…This synergism has been proved in ovarian and triple‐negative breast cancer cells: combinational administration of Dinaciclib (a pan‐CDK inhibitor) and Olaparib (a PARP inhibitor) successfully retarded tumour growth in PDX models 12 . In Dai's research, CDK12 inhibition by small molecule SR‐4835 or its knockdown were both proved to cause dramatic decreases of S2 phosphorylation on the carboxy‐terminal domain of RNA pol II, thus quenching CRCLM 7 . Albeit promising as an experimental therapeutic agent, CDK12 inhibitors are facing impediments in clinical utilization.…”

“…Transcriptional activation, proliferation and outgrowth, cancerous traits, and eventually CRCLM cells were all found to be regulated by CDK12 as well as its functional downstream implementers. These findings protruded the feasibility and superiority of CDK12 as a potent therapeutic target, especially in treating CRCLM 7 …”

“…These findings protruded the feasibility and superiority of CDK12 as a potent therapeutic target, especially in treating CRCLM. 7 CDK12 belongs to the cyclin-dependent kinase family, the subject of vigorous anti-tumour drug discovery research in academia and the pharmaceutical industry. In addition to the direct regulation of oncogenic factors by CDK12-RNAPII (Table 1), the genomic instability induced by CDK12 inactivation contributes to alternatives for cancer therapy.…”

“…6 In this issue of Clinical and Translational Medicine, Dai et al demonstrated the relevance between CRC and hepatic metastasis in a SE-landscape orientation. 7 Cyclindependent kinase 12 (CDK12) was presented as a driving factor for CRCLM, and overexpression of this specific SE component was observed in the pathological process. Besides, several SE-associated oncogenes were determined as critical regulators for forming metastatic-related cellular characters in CRC cells.…”

Bigelovin inhibits hepatocellular carcinoma cell growth and metastasis by regulating the MAPT-mediated Fas/FasL pathway

“…metastatic [1,2]. Reportedly, approximately 41,260 new cases of liver cancer and 30,520 liver cancer-related deaths in the United States in 2022 [3].…”