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Background  KIBRA has been suggested as a key regulator of the Hippo signaling pathway, regulating organ size, cell contact inhibition, tissue regeneration as well as tumorigenesis and cystogenesis. We recently reported that human  KIBRA  expression depends on a complex alternative CpG-rich promoter system. Our current study aimed at the identification of epigenetic mechanisms associated with alterations in  KIBRA  expression regulation.    Results  We identified two separated methylation-sensitive CpG islands located to independent  KIBRA  promoter regions. In vitro promoter methylation analysis using human neuroblastoma (SH-SY5Y) and immortalized kidney cells (IHKE) revealed that total promoter methylation by CpG methyltransferase  Sss I resulted in complete abrogation of transcriptional activity ( p  < 0.001), while partial methylation by  Hpa II selectively repressed  KIBRA  core promoter activity in kidney cells ( p  < 0.001). Cell culture-based experiments demonstrated that 5-azacitidine may be used to restore KIBRA mRNA and protein levels, while overexpression of transcription factor SP1 also induced  KIBRA  upregulation (all  p  < 0.001). Furthermore, SP1 transactivation of  KIBRA  transcription was largely prevented by methylation of  KIBRA  regulatory elements ( p  < 0.001). Analysis of human kidney biopsies revealed that  KIBRA  promoter methylation was associated with human clear cell renal cell carcinoma (ccRCC;  n  = 8 vs 16 controls, OR = 1.921, [CI 95% = 1.369–2.695]). The subsequent determination of KIBRA mRNA levels by real-time PCR in a larger patient sample confirmed significantly reduced KIBRA expression in ccRCC ( n  = 32) compared to non-neoplastic human kidney tissue samples (controls,  n  = 32,  p  < 0.001).    Conclusion  We conclude that epigenetic downregulation of tumor suppressor KIBRA may involve impaired SP1 binding to functional methylation-sensitive  KIBRA  promoter elements as observed in human kidney clear cell carcinoma. Our findings provide a pathophysiological basis for future studies on altered  KIBRA  regulation in clinical disease entities such as renal cancer.    Electronic supplementary material  The online version of this article (10.1186/s13148-017-0415-6) contains supplementary material, which is available to authorized users.

Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma