Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3.
Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3.
复制标题
抑制视黄酸受体 α 磷酸化通过反式激活 miR-3074-5p 靶向 DHRS3 来抑制三阴性乳腺癌的进展
DOI：
10.1186/s13046-021-01941-7
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发表时间：
2021-04-26
期刊：
影响因子：
--
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Lou S;Gao H;Hong H;Zhu Z;Zhao H
Retinoids are promising agents in the treatment of different types of neoplasia including estrogen receptor-positive breast cancers, whereas refractoriness/low sensitivity is observed in triple-negative breast cancer (TNBC) subtype. However, the reason for these diverse retinoid-sensitivity remains elusive. Determinants of retinoid sensitivity were investigated using immunohistochemistry of primary patient samples, and identified retinoic acid receptor α (RARα) as a putative factor. The anti-tumor activity of hypo-phosphorylated RARα was investigated in TNBC cell models and a xenograft mouse model. Next, miRNA sequencing analysis was performed to identify the target miRNA of RARα, and luciferase reporter was used to confirm the direct target gene of miR-3074-5p. We discovered that serine-77 residue of RARα was constantly phosphorylated, which correlated with TNBC’s resistance to retinoids. Overexpression of a phosphorylation-defective mutant RARαS77A mimicked activated RARα and repressed TNBC cell progression both in vitro and in vivo, via activating cell cycle arrest, apoptosis, and cytotoxic autophagy, independent of RARα agonists. We further revealed that the anti-tumor action of RARαS77A was, at least in part, mediated by the up-regulation of miR-3074-5p, which directly targeted DHRS3, a reductase negatively associated with TNBC patient survival. Our results suggest that the inhibition of RARαS77 phosphorylation by either expressing RARαS77A or inhibiting RARα’s phosphokinase CDK7, can bypass RA stimuli to transactivate tumor-suppressive miR-3074-5p and reduce oncogenic DHRS3, thus overcoming the RA-resistance of TNBC. The novel regulatory network, involving RARαS77 phosphorylation, miR-3074-5p, and DHRS3, emerges as a new target for TNBC treatment. The online version contains supplementary material available at 10.1186/s13046-021-01941-7.
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影响因子：
64.8
作者：
Kwiatkowski, Nicholas;Zhang, Tinghu;Rahl, Peter B.;Abraham, Brian J.;Reddy, Jessica;Ficarro, Scott B.;Dastur, Anahita;Amzallag, Arnaud;Ramaswamy, Sridhar;Tesar, Bethany;Jenkins, Catherine E.;Hannett, Nancy M.;McMillin, Douglas;Sanda, Takaomi;Sim, Taebo;Kim, Nam Doo;Look, Thomas;Mitsiades, Constantine S.;Weng, Andrew P.;Brown, Jennifer R.;Benes, Cyril H.;Marto, Jarrod A.;Young, Richard A.;Gray, Nathanael S.
通讯作者：
Gray, Nathanael S.
影响因子：
5.8
作者：
Crowe DL;Kim R
通讯作者：
Kim R
影响因子：
1.6
作者：
Ge YZ;Xu LW;Xu Z;Wu R;Xin H;Zhu M;Lu TZ;Geng LG;Liu H;Zhou CC;Yu P;Zhao YC;Hu ZK;Zhao Y;Zhou LH;Wu JP;Li WC;Zhu JG;Jia RP
通讯作者：
Jia RP
影响因子：
64.5
作者：
FISHER, RP;MORGAN, DO
通讯作者：
MORGAN, DO
影响因子：
20.3
作者：
Gianni, M;Calzi, ML;Garattini, E
通讯作者：
Garattini, E