Cell-specific Kaiso (ZBTB33) Regulation of Cell Cycle through Cyclin D1 and Cyclin E1

The correlation between aberrant DNA methylation with cancer promotion and progression has prompted an interest in discerning the associated regulatory mechanisms. Kaiso (ZBTB33) is a specialized transcription factor that selectively recognizes methylated CpG-containing sites as well as a sequence-specific DNA target. Increasing reports link ZBTB33 overexpression and transcriptional activities with metastatic potential and poor prognosis in cancer, although there is little mechanistic insight into how cells harness ZBTB33 transcriptional capabilities to promote and progress disease. Here we report mechanistic details for how ZBTB33 mediates cell-specific cell cycle regulation. By utilizing ZBTB33 depletion and overexpression studies, it was determined that in HeLa cells ZBTB33 directly occupies the promoters of cyclin D1 and cyclin E1, inducing proliferation by promoting retinoblastoma phosphorylation and allowing for E2F transcriptional activity that accelerates G₁- to S-phase transition. Conversely, in HEK293 cells ZBTB33 indirectly regulates cyclin E abundance resulting in reduced retinoblastoma phosphorylation, decreased E2F activity, and decelerated G₁ transition. Thus, we identified a novel mechanism by which ZBTB33 mediates the cyclin D1/cyclin E1/RB1/E2F pathway, controlling passage through the G₁ restriction point and accelerating cancer cell proliferation.