We conducted this study to examine CDK8 expression in a large cohort of colorectal cancers which were annotated with clinical, pathologic and molecular information. A copy number gain of 13q where the CDK8
gene resides has been reported as a frequent event in the transition from colorectal adenoma to carcinoma.36
CDK8 is commonly expressed in colon cancer and its overexpression highly correlates to copy number gain of its locus (13q12.13).4
We have found that CDK8 expression is associated with high β-catenin activity as well as other molecular markers of significance in colon cancer such as fatty acid synthase (FASN) and p53 expression. Importantly, CDK8 expression is significantly associated with a poor patient outcome in human colon tumors independent of stage and other potential predictors of patient outcome. In contrast to colon cancer patients, tumoral CDK8 status does not appear to predict outcome among rectal cancer patients. Our findings support a role for CDK8 in human colon cancer and define CDK8 positive tumors as having a unique clinico-pathological footprint.
A role for CDK8 in β-catenin driven transcription has been documented in colon cancer cell lines. 7
Furthermore, in Drosophila melanogaster
, additional Mediator protein subunits MED12 and MED13, drive β-catenin activity.31
Given the importance of the Wnt/β-catenin pathway in human tumorigenesis, our data showing an association between CDK8 expression and β-catenin activity are particularly intriguing. While it is possible that the presence of poor quality specimens, which tended to be negative for any markers, might have driven the relationship between CDK8 and β-catenin nuclear and cytoplasmic expressions towards a concordant pattern, the association between CDK8 and loss of β-catenin membrane expression was reassuring for a true relationship. Our finding raises the possibility that CDK8 may affect β-catenin protein stability or nuclear retention/localization. Further studies will be of interest to determine whether the association between CDK8 expression and β-catenin activity is correlative or causative. These results support a role for CDK8 in β-catenin driven human malignancies and lend credence to the possibility of CDK8 being a therapeutic target for β-catenin driven cancers.
Over the past decade, cyclin-dependent kinases (CDKs), have been shown to be hyperactivated in multiple tumor types.37
As such, there are a number of CDK inhibitors currently being developed and undergoing clinical testing in several human malignancies, including colon cancer.37
Previous studies have shown that CDK8 kinase activity is critical for regulating β-catenin activity in colon cancer.4, 5
Therefore, it will be of interest to test such small molecules for their ability to inhibit CDK8. Our results identify a patient population that is characterized by high levels of CDK8 activity, providing a potential patient pool that may be distinctly responsive to CDK inhibitor therapy. Future studies focusing on the ability of known CDK inhibitors to target CDK8 will be particularly useful in assessing whether CDK8 expression can serve as a therapeutic biomarker for clinical trials involving CDK inhibitory molecules.
Examining molecular biomarkers is important in cancer research.38-46
Our data suggest that CDK8 expression may be associated with a poor patient prognosis, independently of potential confounders, including β-catenin. These results are consistent with the fact that CDK8 is involved in regulating other pathways besides Wnt/β-catenin and suggest that CDK8 inhibition may also be useful in tumors which may not be driven by β-catenin hyperactivity. Nonetheless, our findings need to be confirmed by independent studies.
In addition to the potential association with β-catenin activity and patient outcome, we have found that CDK8 expression is potentially associated with two other important molecules related to cancer; p53 and FASN (fatty acid synthase).22, 32-35
The potential association between CDK8 and p53 is particularly intriguing, as a previous study has suggested that increased binding of CDK8 to p53 target genes correlates positively with transcriptional strength.9
Given the important role of TP53
mutation in multiple human tumors, it will be of great interest to further study the association between CDK8 and TP53
mutation in driving human malignancies. The relationship between CDK8 expression and FASN may be more indirect given that the two proteins do not share a common intracellular space. FASN is activated in states of energy excess and overexpressed in multiple human malignancies, including colorectal cancer.22, 32-35
Although no studies have directly linked CDK8 to energy balance, our data are consistent with the pleiotropic roles of CDKs in cellular homeostasis and may open new avenues of study in CDK8 and energy metabolism. These associations between CDK8 and β-catenin activity, p53 expression and FASN expression define a set of molecular features of CDK8-positive tumors characterized by increased oncogenic activity.
We found an intriguing association between female gender and CDK8 expression. Female gender has been known to be associated with some molecular events such as CpG island methylation. In particular, the CpG island methylator phenotype (CIMP) has been associated with female gender.19, 47
Postmenopausal hormone use has been known to modify the risk of developing colorectal cancer,48
as well as risk of colorectal cancer mortality.49, 50
Therefore, it is conceivable that a different hormonal environment between male and female may predispose to different molecular aberrations, including CDK8 amplification and overexpression. Further studies are necessary for understanding of biologic basis of the association between female gender and CDK8 expression in colorectal cancer.
There are limitations in this study. For example, data on cancer treatment were limited. Nonetheless, it is unlikely that chemotherapy use substantially differed according to CDK8 status, since such data were unavailable for clinicians. In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given the median survival for metastatic colon cancer was approximately 10 to 12 months during much of the time period of this study, colorectal cancer-specific survival should be a reasonable surrogate for cancer-specific outcomes.
There are advantages in utilizing the database of the two independent prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study to examine significance of tumoral CDK8 expression. Anthropometric measurements, family history of cancer, other clinical information, pathologic and tumor staging data, and tumoral molecular features were prospectively collected, and entered into the database blinded to patient outcome. Cohort participants who developed colon cancer were treated at hospitals throughout the United States, and thus more representative of colorectal cancers in the general population, than studies based on a single to few hospitals. Tumor specimen procurement rate has been 60-70%, and there were no demographic difference between cases with tumor tissue analyzed and those without tumor tissue analyzed.10
In addition, our rich tumor database enabled us to simultaneously assess pathologic and molecular features of tumor and control for confounding by tumoral variables. Thus, our study is unique in terms of comprehensiveness of tumor database.
In summary, we have conducted the first population-based study to assess CDK8 expression in a large cohort of colorectal cancers. Our findings show that CDK8 is expressed in a high fraction of colorectal cancers and that CDK8-positive colon cancers are significantly associated with a poor patient prognosis. These data define a molecular and clinical landscape for CDK8-positive colon cancers. Given the number of CDK inhibitors undergoing clinical trials for a variety of human malignancies, these findings may be of great use in defining patients that may be distinctly susceptible to CDK small molecule based therapies.