CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma

BACKGROUND: Dysregulation of polycomb chromobox (CBX) proteins that mediate epigenetic gene silencing contributes to the progression of human cancers. Yet their roles in clear cell renal cell carcinoma (ccRCC) remain to be explored. METHODS: The expression of CBX4 and its clinical significance were determined by qRT-PCR, western blot, immunohistochemistry and statistical analyses. The biological function of CBX4 in ccRCC tumor growth and metastasis and the underlying mechanism were investigated using in vitro and in vivo models. FINDINGS: CBX4 exerts oncogenic activities in ccRCC via interaction with HDAC1 to transcriptionally suppress tumor suppressor KLF6. CBX4 expression is increased in ccRCC and correlated with poor prognosis in two independent cohorts containing 840 patients. High CBX4 expression is significantly associated with Fuhrman grade and tumor lymph node invasion. CBX4 overexpression promotes tumor growth and metastasis, whereas CBX4 knockdown results in the opposite phenotypes. Mechanistically, CBX4 downregulates KLF6 via repressing the transcriptional activity of its promoter. Further studies show that CBX4 physically binds to HDAC1 to maintain its localization on the KLF6 promoter. Ectopic expression of KLF6 or disruption of CBX4-HDAC1 interaction attenuates CBX4-mediated cell growth and migration. Furthermore, CBX4 depletion markedly enhances the histone deacetylase inhibitor (HDACi)-induced cell apoptosis and suppression of tumor growth. INTERPRETATION: Our data suggest CBX4 as an oncogene with prognostic potential in ccRCC. The newly identified CBX4/HDAC1/KLF6 axis may represent a potential therapeutic target for the clinical intervention of ccRCC.