Androgen-induced miR-135a acts as a tumor suppressor through downregulating RBAK and MMP11, and mediates resistance to androgen deprivation therapy.
The main challenge in the treatment of prostate cancer (PCa) is that the majority of patients inevitably develop resistance to androgen deprivation. However, the mechanisms involved in hormone independent behavior of PCa remain unclear. In the present study, we identified androgen-induced miR-135a as a direct target of AR. Functional studies revealed that overexpression of miR-135a could significantly decrease cell proliferation and migration, and induce cell cycle arrest and apoptosis in PCa. We identified RBAK and MMP11 as direct targets of miR-135a in PCa by integrating bioinformatics analysis and experimental assays. Mechanistically, miR-135a repressed PCa migration through downregulating MMP11 and induced PCa cell cycle arrest and apoptosis by suppressing RBAK. Consistently, inverse correlations were also observed between the expression of miR-135a and RBAK or MMP11 in PCa samples. In addition, low miR-135a and high RBAK and MMP11 expression were positively correlated with PCa progression. Also, PI3K/AKT pathway was confirmed to be an upstream regulation signaling of miR-135a in androgen-independent cell lines. Accordingly, we reported a resistance mechanism to androgen deprivation therapy (ADT) mediated by miR-135a which might be downregulated by androgen depletion and/or PI3K/AKT hyperactivation, in castration-resistant prostate cancer (CRPC), thus promoting tumor progression. Taken together, miR-135a may represent a new diagnostic and therapeutic biomarker for castration-resistant PCa.
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Xuechao
X
Wan
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Honglei
H
Pu
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Wenhua
W
Huang
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Shu
S
Yang
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Yalong
Y
Zhang
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Zhe
Z
Kong
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.
Zhuoran
Z
Yang
Center of Translational Medicine, Central Hospital of Zibo, Zibo, Shangdong, 255036, PR China.
Peiqing
P
Zhao
Center of Translational Medicine, Central Hospital of Zibo, Zibo, Shangdong, 255036, PR China.
Ao
A
Li
Center of Translational Medicine, Central Hospital of Zibo, Zibo, Shangdong, 255036, PR China.
Tao
T
Li
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Science, Fudan University, Shanghai, 200433, PR China.|Key Laboratory of Reproduction Regulation of NPFPC, Fudan University, Shanghai, 200433, PR China.
Yao
Y
Li
D000726:Androgen Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D008297:Male; D053507:Matrix Metalloproteinase 11 / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics*
D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; C529062:RBaK protein, human; D012097:Repressor Proteins; C511771:MMP11 protein, human; D053507:Matrix Metalloproteinase 11
MMP11; PI3K/AKT; RBAK; androgen receptor; miR-135a