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c-Myc suppresses miR-451?YWTAZ/AKT axis via recruiting HDAC3 in acute myeloid
leukemia
#MMPMID27764807
Su R
; Gong JN
; Chen MT
; Song L
; Shen C
; Zhang XH
; Yin XL
; Ning HM
; Liu B
; Wang F
; Ma YN
; Zhao HL
; Yu J
; Zhang JW
Oncotarget
2016[Nov]; 7
(47
): 77430-77443
PMID27764807
show ga
Aberrant activation of c-Myc plays an important oncogenic role via regulating a
series of coding and non-coding genes in acute myeloid leukemia (AML). Histone
deacetylases (HDACs) can remove acetyl group from histone and regulate gene
expression via changing chromatin structure. Here, we found miR-451 is abnormally
down-regulated in AML patient samples; c-Myc recruits HDAC3 to form a
transcriptional suppressor complex, co-localizes on the miR-451 promoter,
epigenetically inhibits its transcription and finally induces its downregulation
in AML. Furthermore, our in vitro and in vivo results suggest that miR-451
functions as a tumor suppressor via promoting apoptosis and suppressing malignant
cell proliferation. The mechanistic study demonstrated that miR-451 directly
targets YWHAZ mRNA and suppresses YWHAZ/AKT signaling in AML. Knockdown of c-Myc
results in restoration of miR-451 and inhibition of YWHAZ/AKT signaling. In AML
patients, low level of miR-451 is negatively correlated with high levels of c-Myc
and YWHAZ, while c-Myc level is positively related to YWHAZ expression. These
results suggested that c-Myc?miR-451?YWHAZ/AKT cascade might play a crucial role
during leukemogenesis, and reintroduction of miR-451 could be as a potential
strategy for AML therapy.
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