Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression
Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression
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阻断 PPARγ 相互作用有助于 Nur77 阻断脂肪酸摄取并抑制乳腺癌进展。
DOI：
10.1073/pnas.2002997117
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发表时间：
2020-11-03
影响因子：
11.1
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
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作者：
Yang, Peng-Bo;Hou, Pei-Pei;Wu, Qiao
核受体Nur77参与多种代谢调节，在肿瘤发生中起着矛盾的作用。在这里，我们证明了在两个小鼠模型中，Nur77基因的敲除刺激了乳腺肿瘤的发展，这种情况将被Nur77基因在乳腺组织中的特定重新表达所逆转。在机制上，Nur77与CD36和FABP4的启动子相互作用，并招募辅阻遏子SWI/SNF复合体来抑制它们的转录，从而阻碍脂肪酸的摄取，从而抑制细胞增殖。过氧化物酶体增殖物激活受体-γ(PPAR-Gamma)通过与Nur77结合，促进泛素连接酶Trim13介导的泛素化和Nur77的降解，在这一过程中起到拮抗作用。晶体学和功能分析表明，NUR77靶向化合物Csn-B促进了NUR77同源二聚体的形成，阻止了PPAR通过空间位阻与γ结合，从而增强了NUR77‘S对乳腺癌的抑制作用。因此，我们的研究揭示了Nur77通过阻止脂肪酸摄取在乳腺癌中的调节作用。
Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPAR gamma binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.