PHD1 regulates p53-mediated colorectal cancer chemoresistance.
PHD1 regulates p53-mediated colorectal cancer chemoresistance.
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DOI：
10.15252/emmm.201505492
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发表时间：
2015-10
影响因子：
11.1
通讯作者：
Mazzone M
中科院分区：
文献类型：
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作者：
Deschoemaeker S;Di Conza G;Lilla S;Martín-Pérez R;Mennerich D;Boon L;Hendrikx S;Maddocks OD;Marx C;Radhakrishnan P;Prenen H;Schneider M;Myllyharju J;Kietzmann T;Vousden KH;Zanivan S;Mazzone M
克服化疗耐药性是结直肠癌（CRC）治疗的主要挑战，特别是因为潜在的分子机制尚不清楚。我们发现，脯氨酰羟化酶结构域蛋白PHD 1的沉默，而不是PHD 2或PHD 3，防止p53激活化疗后，在不同的CRC细胞系，从而抑制DNA修复，有利于细胞死亡。从机制上讲，PHD 1活性以羟基化依赖性方式增强p53与p38α激酶的结合。在p53-p38α相互作用和化疗损伤后，p53可以在丝氨酸15处磷酸化，从而被激活。活性p53通过与DNA解旋酶XPB相互作用允许核苷酸切除修复，从而保护免受化疗诱导的细胞凋亡。与该观察结果雅阁，PHD 1敲低极大地使小鼠中CRC对5-FU敏感。我们认为PHD 1是CRC耐药机制的一部分，支持PHD 1特异性抑制剂的合理药物设计及其与化疗联合使用。
Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation-dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy-induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5-FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1-specific inhibitors and their use in combination with chemotherapy.