In a recent study, a research team led by Margaret McLaughlin-Drubin, PhD, and Karl Munger, PhD, Division of Infectious Diseases, Department of Medicine, discovered a novel therapeutic “Achilles heel” of cervical carcinoma cell lines. They found that the activity of the histone lysine demethylase, KDM6B (a type of enzyme involved in epigenetic modification), is required for the survival of a number of cervical carcinoma lines. This “addiction” to KDM6B expression is caused by the human papillomavirus (HPV) encoded E7 oncoprotein.
E7 oncoprotein expression causes HPV-associated tumors to express high levels of a tumor suppressor protein called p16INK4A. Induction of p16INK4A by E7 is mediated by the KDM6B histone lysine demethylase. p16INK4A acts as an inhibitor of cyclin-dependent kinases 4 and 6/cyclin D complexes, which in turn regulate the activity of the retinoblastoma tumor suppressor. The retinoblastoma tumor suppressor is a key regulator of oncogene-induced senescence—a fail-safe mechanism that protects cells from unrestrained proliferation.
The research team found that in cervical cancers where the retinoblastoma tumor suppressor is inactivated, and the oncogene-induced senescence response, therefore, is rendered inactive, cyclin-dependent kinases 4 and 6 activity need to be inhibited by p16INK4A for cervical cancer cells to survive. They found that p16INK4A is the key mediator of KDM6B addiction in HPV-associated tumor lines.
Since some cervical carcinoma lines undergo cell death when treated with a small-molecule KDM6 inhibitor, this study suggests that inhibiting KDM6 may be further explored as a treatment for high-risk HPV-associated lesions and cancers.
“This study not only shows that a well-established cervical cancer biomarker, p16INK4A, is also a therapeutic target, but challenges the current paradigm regarding the biological activity of retinoblastoma tumor suppressor pathway,” said McLaughlin-Drubin.
Added Munger, “We hope that what we have learned from studying HPV-associated cancers can also be applied to other tumor types.”
The study was published the week of Sept.16, 2013, in Proceedings of the National Academy of Sciences.