DNMT1-maintained hypermethylation of Krüppel-like factor 5 involves in the progression of clear cell renal cell carcinoma
DNA (Cytosine-5-)-Methyltransferase 1
0301 basic medicine
Mice, Inbred BALB C
0303 health sciences
Cell Survival
Blotting, Western
Kruppel-Like Transcription Factors
Mice, Nude
DNA Methylation
In Vitro Techniques
Real-Time Polymerase Chain Reaction
Immunohistochemistry
Kidney Neoplasms
3. Good health
Gene Expression Regulation, Neoplastic
Mice
03 medical and health sciences
HEK293 Cells
Cell Line, Tumor
Animals
Humans
Original Article
Female
Carcinoma, Renal Cell
Cell Proliferation
DOI:
10.1038/cddis.2017.323
Publication Date:
2017-07-27T12:42:59Z
AUTHORS (10)
ABSTRACT
AbstractClear cell renal cell carcinoma (ccRCC) is the major subtype of renal cell carcinoma (RCC) that is resistant to conventional radiation and chemotherapy. It is a challenge to explore effective therapeutic targets and drugs for this kind of cancer. Transcription factor Krüppel-like factor 5 (KLF5) exerts diverse functions in various tumor types. By analyzing cohorts of the Cancer Genome Atlas (TCGA) data sets, we find that KLF5 expression is suppressed in ccRCC patients and higher level of KLF5 expression is associated with better prognostic outcome. Our further investigations demonstrate thatKLF5genomic loci are hypermethylated at proximal exon 4 and suppression of DNA methyltransferase 1 (DNMT1) expression by ShRNAs or a methylation inhibitor 5-Aza-CdR can recover KLF5 expression. Meanwhile, there is a negative correlation between expressions of KLF5 and DNMT1 in ccRCC tissues. Ectopic KLF5 expression inhibits ccRCC cell proliferation and migration/invasionin vitroand decreases xenograft growth and metastasisin vivo. Moreover, 5-Aza-CdR, a chemotherapy drug as DNMTs’ inhibitor that can induce KLF5 expression, suppresses ccRCC cell growth, while knockdown of KLF5 abolishes 5-Aza-CdR-induced growth inhibition. Collectively, our data demonstrate that KLF5 inhibits ccRCC growth as a tumor suppressor and highlight the potential of 5-Aza-CdR to release KLF5 expression as a therapeutic modality for the treatment of ccRCC.
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