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2017 ; 16
(1
): 56
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BMI1, a new target of CK2?
#MMPMID28270146
Banerjee Mustafi S
; Chakraborty PK
; Dwivedi SK
; Ding K
; Moxley KM
; Mukherjee P
; Bhattacharya R
Mol Cancer
2017[Mar]; 16
(1
): 56
PMID28270146
show ga
BACKGROUND: The polycomb group protein, BMI1 plays important roles in chromatin
modification, stem cell function, DNA damage repair and mitochondrial
bioenergetics. Such diverse cellular functions of BMI1 could be, in part, due to
post-translational modifications, especially phosphorylation. To date, AKT has
been reported as a kinase that by site specific phosphorylation of BMI1 modulates
its oncogenic functions. METHODS: Immunoprecipitation in conjunction with kinase
assay and mass spectrometry was used to determine association with and site
specific phosphorylation of BMI1 by CK2?. Functional implications of the
BMI1/CK2? axis was examined in cancer cells utilizing siRNA and exogenous gene
expression followed by biochemical and phenotypic studies. Correlations between
expression of CK2? and BMI1 were determined from cell lines and formalin fixed
paraffin embedded tissues representing the normal fallopian tube epithelium and
high grade serous ovarian cancer samples. RESULTS: Here we report that CK2?, a
nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined
by in-vitro/ex-vivo kinase assay and mass spectrometry. In ovarian cancer cell
lines, expression of CK2? correlated with the phospho-species, as well as basal
BMI1 levels. Preventing phosphorylation of BMI1 at Serine 110 significantly
decreased half-life and stability of the protein. Additionally, re-expression of
the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in
endogenous BMI1 silenced cancer cells leading us to speculate that CK2?-mediated
phosphorylation stabilizes BMI1 and promotes its oncogenic function. Clinically,
compared to normal fallopian tube epithelial tissues, the expression of both BMI1
and CK2? were significantly higher in tumor tissues obtained from high-grade
serous ovarian cancer patients. Among tumor samples, the expression of BMI1 and
CK2? positively correlated (Spearman coefficient =?0.62, P?=?0.0021) with each
other. CONCLUSION: Taken together, our findings establish an important regulatory
role of CK2? on BMI1 phosphorylation and stability and implicate the CK2?/BMI1
axis in ovarian cancer.
|Casein Kinase II/metabolism
[MESH]
|Cell Line, Tumor
[MESH]
|Female
[MESH]
|Humans
[MESH]
|Mitogen-Activated Protein Kinase 7/metabolism
[MESH]
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