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2017 ; 8
(6
): e2882
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Cdc20 directs proteasome-mediated degradation of the tumor suppressor SMAR1 in
higher grades of cancer through the anaphase promoting complex
#MMPMID28617439
Paul D
; Ghorai S
; Dinesh US
; Shetty P
; Chattopadhyay S
; Santra MK
Cell Death Dis
2017[Jun]; 8
(6
): e2882
PMID28617439
show ga
The Tumor suppressor SMAR1 (scaffold matrix attachment region binding protein 1)
has a crucial role in maintaining genomic stability, cell cycle progression and
apoptosis.Our previous finding showed that it is highly suppressed in higher
grade of cancer. However, the underlying mechanism of this suppression was not
well understood. In this study, we show that SMAR1 expression levels are
controlled at the proteasomal level by five RING finger E3 ubiquitin ligases
including, Cdc20, a substrate receptor of ubiquitin ligase APC/C complex. We
found that Cdc20 binds and promotes proteasomal degradation of SMAR1 in a D-box
motif dependent manner. Further, our results demonstrated that Cdc20 promotes
proteasomal degradation of SMAR1 through K48-linked specific polyubiquitylation,
and that short hairpin RNA mediated inactivation of Cdc20 leads to significant
stabilization of SMAR1. These findings suggest that Cdc20 is responsible for
maintaining the cellular levels of SMAR1. However, since Cdc20 fails to target
SMAR1 upon exposure to genotoxic stresses, SMAR1 helps to maintain genomic
stability under these conditions through its DNA damage repair activity.
Interestingly, Cdc20-mediated degradation of SMAR1 promotes cell migration and
invasion.The reciprocal relationship of the duo is evident in breast cancer cell
lines as well as in patient samples, suggesting that Cdc20 functions as an
important negative regulator of SMAR1 in higher grades of cancer. Our study
reveals for the first time, the molecular mechanism associated with lower levels
of expression of the important tumor suppressor SMAR1 in higher grades of breast
cancer.