The emerging roles of CDK12 in tumorigenesis

Abstract

Cyclin-dependent kinases (CDKs) are key regulators of both cell cycle progression and transcription. Since dysregulation of CDKs is a frequently occurring event driving tumorigenesis, CDKs have been tested extensively as targets for cancer therapy. Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase which participates in various cellular processes, including DNA damage response, development and cellular differentiation, as well as splicing and pre-mRNA processing. CDK12 mutations and amplification have been recently reported in different types of malignancies, including loss-of-function mutations in high-grade serous ovarian carcinomas, and that has led to assumption that CDK12 is a tumor suppressor. On the contrary, CDK12 overexpression in other tumors suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. In this review, we discuss current knowledge concerning the role of CDK12 in ovarian and breast tumorigenesis and the potential for chemical inhibitors of CDK12 in future cancer treatment.

CAncer bioMarker Prediction Pipeline (CAMPP) - A standardised and user-friendly framework for the analysis of quantitative biological data

“…The set of 20 consensus genes encompassed many well-known genes with the potential to distinguish subtypes. In addition to three pam50 genes; ERBB2, ESR1 and FOXA1 (Parker, et al, 2009), the consensus set included; C1orf64 (ER-related factor, ERRF) which was down-regulated in TNBC, in accordance with literature (Naderi, 2017;Su, et al, 2012), CDK12, which was up-regulated in Her2 samples, supported by literature indicating that a total of 71% of Her2-enriched tumours over-express this gene (Paculova and Kohoutek, 2017). Other genes of interest were CYP2B6 (Lo, et al, 2010), MYLK3 (D'Amato, et al, 2015 and SLURP1 (Gao, et al, 2014).…”

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

“…We see mutations in oncogenes and tumor-suppressor genes in HepG2, such as NRAS (Pylayeva-Gupta et al 2011), STK11/LKB1 (Zhou et al 2014), and PREX2 (Berger et al 2012;Yang et al 2016), as well as in the Wnt-pathway gene CTNNB1 due to the presence of either HepG2-specific protein-altering changes or small-scale structural changes (Table S5, Table S6, Dataset 1, Dataset 4, Supplemental Data). Moreover, we also identified mutations in genes recently found to play critical roles in driving cancer such as CDK12 (Paculová and Kohoutek 2017) and IKBKB (Xia et al 2012;Kai et al 2014). These mutations also implicate the dis-regulation of their associated molecular pathways in HepG2.…”

“…The gene overlap between HepG2 PPA and the Sanger Cancer Gene Census is 19 (Table S6). HepG2 PPA variants include oncogenes and tumor suppressors such as NRAS (Pylayeva-Gupta et al 2011), STK11/LKB1 (Zhou et al 2014), and PREX2 (Berger et al 2012;Yang et al 2016) as well as other genes recently found to play critical roles in driving cancer such as CDK12 (Paculová and Kohoutek 2017) and IKBKB (Xia et al 2012;Kai et al 2014). RP1L1, which was recently found to be significantly mutated in hepatocellular carcinoma (Cancer Genome Atlas Research Network 2017) is also present among the PPA variants.…”

The role of cyclin‐dependent kinases in oral potentially malignant disorders and oral squamous cell carcinoma

“…CDK12 has roles in the DNA damage response as well as in cellular and developmental differentiation; however, the exact mechanism by which CDK12 acts in the transcriptional regulation of these genes is not yet fully understood. Overexpression of CDK12 has been demonstrated in breast and ovarian carcinogenesis, but has not yet been investigated in OSCC …”

“…Overexpression of CDK12 has been demonstrated in breast and ovarian carcinogenesis, but has not yet been investigated in OSCC. 39 Overexpression of CDKs, in particular CDK4 and CDK6, has been shown to contribute to cell cycle dysfunction in a range of cancer types. Currently, there is minimal evidence regarding the role of CDKs in the development and progression of OSCC; however, we suggest that it is a promising area of investigation.…”