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Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma
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Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma
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Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma
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Journal Article
Promoter methylation inhibits expression of tumor suppressor KIBRA in human clear cell renal cell carcinoma
2017
Overview
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.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Analysis
/ Biomedical and Life Sciences
/ Cancer
/ Cancer epigenetics and diagnostics
/ Carcinoma, Renal Cell - genetics
/ Carcinoma, Renal Cell - metabolism
/ Cellular signal transduction
/ Clear cell-type renal cell carcinoma
/ DNA
/ Female
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Intracellular Signaling Peptides and Proteins - genetics
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Kidney Neoplasms - metabolism
/ Kinases
/ Male
/ Phosphoproteins - metabolism
/ Proteins
/ Sp1 Transcription Factor - metabolism
/ Tumor
/ Tumors
/ WWC1
