Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UMLS:C0026764 (
multiple myeloma
)
36,148
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Multiple myeloma
(MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of
MIR145-3p
(microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of
MIR145-3p
expression was associated with disease progression in human MM.
MIR145-3p
triggered autophagic flux through direct targeting of
HDAC4
(histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing
HDAC4
recapitulated the effects of
MIR145-3p
, whereas enforced expression of
HDAC4
abrogated the effects of
MIR145-3p
. Furthermore, we showed that suppression of
HDAC4
by
MIR145-3p
resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that
MIR145-3p
mimic could potentiate the anti-MM activity of bortezomib in both
in vitro
and
in vivo
experiments. Overall, our findings indicate that
MIR145-3p
exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that
MIR145-3p
-based targeted therapy would represent a novel strategy for MM treatment.
Abbreviations:
3-MA: 3-methyladenine; 3'-UTR: 3'-untranslated region; 7-AAD: 7-aminoactinomycin D; ACTB: actin beta; ANXA5: annexin A5; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; BAF: bafilomycin A
1
; BCL2L11: BCL2 like 11; Bort: bortezomib; CASP3: caspase 3; CCK-8: Cell Counting Kit-8; CQ: chloroquine; Ct: threshold cycle; ctrl: control; DAPI: 4',6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HDAC4: histone deacetylase 4; ISS: International Staging System; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNAs: microRNAs;
MIR145-3p
: microRNA 145-3p; MM:
multiple myeloma
; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PCs: plasma cells; PFS: progression-free survival; qRT-PCR: quantitative reverse transcription PCR; RPS6KB1: ribosomal protein S6 kinase B1; SD: standard deviation; siRNA: small interfering RNA; SQSTM1: sequestosome 1;
STV
: starvation; TUBB: tubulin beta class I.
...
PMID:
MIR145-3p
promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting
HDAC4
. 3124 29
