CDK12 Gene Editing    

Cyclin-dependent kinase (Cdk) 12 is a protein kinase belonging to the Cdk family. CDK12 engages in a variety of biological functions, from transcription, post-transcriptional modification, cell cycle, and translation to cellular proliferation. Besides, it regulates the expression of cancer-related genes involved in DNA damage response (DDR) and replication, which are responsible for maintaining genomic stability. CDK12 appears as an oncogene or tumor suppressor in different cellular environments, where its dysregulation leads to tumorigenesis.

CDK12 in Human Tumors

CDK12 is located on chromosome 17 (17p21), which contains several candidate genes for breast cancer susceptibility and it is co-amplified with the tyrosine kinase receptor ERBB2, amplified and overexpressed in 20% of breast cancers. CDK12 is altered by amplifications, out-of-frame rearrangements and mutations in different tumor types, although the relationship between these modifications and altered gene expression and/or relevance to cancer is not yet clear. CDK-12 gene amplification is associated with malignant transformation and progression of carcinoma ex pleomorphic adenoma along with other gene copy number alterations (MLLT6, KDM5A, Laps1 and ERBB2). CDK-12 out-of-frame rearrangements were detected in breast micropapillary carcinomas. As CDK12 maps to the smallest region of amplification of the HER amplicon, the disruption of CDK12 was caused by the copy number breakpoint within the amplicon. Re-analysis of available sequencing data showed a similar rearrangement in 2.6% of unselected breast cancers and 13% of the HER2-amplified breast cancers; 5% of HER2-amplified gastric cancers had CDK12 DNA rearrangements.

In triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), CDK12 is a tumor suppressor. CDK12 is necessary for the expression of DDR genes and it is essential for HR mediated DNA repair. Therefore, CDK12 loss leads to increased genomic instability, which is a typical feature of these tumors and represents one of the hallmarks of cancer progression. Cdk12 loss of function mutation or inhibition makes cells sensitive to PARP1/2 inhibitors. In another case, CDK12 has properties that resemble oncogenes. CDK12 amplification, causing its overexpression, correlates with more aggressive tumor progression in HER2-positive breast cancers. CDK12 is highly active in these tumors, and it has been considered as a druggable target in HER2-amplified breast cancer. This view might be supported by the fact that CDK12 inhibition limits the growth of cancer cells. The concept of transcriptional addiction describes the dependence of cancer cells on a certain transcriptional regulator that maintains an altered transcriptional program. According to this concept, inhibitors of CDK12-related transcriptional kinases CDK7 and CDK9 reduce the proliferation of cancer cells and are currently being tested as anti-tumor drugs. In conclusion, the dual role of CDK12 in cancerogenesis could be explained by the fact that CDK12 is essential for the expression of both tumor suppressors and oncogenes, and it is involved in a variety of cellular processes.

Figure 1. Role of CDK12 in cancer. (Paculová H, Kohoutek J., 2017)

CDK12 as A Therapeutic Target

In addition to its potential role as a clinical biomarker, recent studies have emphasized CDK12 as a therapeutic target for cancer. Inhibition of transcriptional CDKs may be an effective strategy to overcome drug resistance to targeted therapies, including crizotinib and erlotinib. Many other studies have identified specific genetic or cellular contexts that confer enhanced sensitivity to CDK12 inhibition, including MYC dependency, PARP inhibition and EWS/FLI rearrangement.

CDK12 Gene Editing Services

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control CDK12 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Service	Details	Alternative cell lines or animal species
CDK12 Gene Editing Cell Line Generation	gRNA design and synthesis Transfect the cell lines you're interested Select the high expression cells and sort monoclonal cell Validate the knockout/knockin/point mutation of CDK12 by PCR and sequencing Provide cryogenically preserved vials of stable cells and final reports	HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
CDK12 Gene Editing Animal Model Generation	CDK12 gene conventional knockout animals CDK12 gene conditional knockout animals CDK12 point mutation animals CDK12 knockin animals	Mouse, rat, rabbit, zebrafish, C. elegans, etc.

Related Products at CRISPR/Cas9 Platform^CB