Derepression of LOXL4 inhibits liver cancer growth by reactivating compromised p53
Derepression of LOXL4 inhibits liver cancer growth by reactivating compromised p53
复制标题
LOXL4 的去抑制可通过重新激活受损的 p53 来抑制肝癌生长。
DOI：
10.1038/s41418-019-0293-x
复制
发表时间：
2019-11-01
影响因子：
12.4
通讯作者：
Wang, Xiong-Jun
中科院分区：
文献类型：
--
作者：
Shao, Jialiang;Lu, Jiongjiong;Wang, Xiong-Jun
TP 53是人类癌症中最常见的突变基因，而具有野生型TP 53的肿瘤发展出替代策略来生存。鉴定p53再激活的新调节剂将极大地有助于癌症治疗的发展。在筛选肝癌细胞的整个基因组后，我们确定赖氨酰氧化酶样4（LOXL 4）作为p53激活的新调节剂。我们发现5-氮杂胞苷（5-aza-CR）诱导LOXL 4上调，LOXL 4随后通过其低等电点区域结合p53的碱性结构域。L0 XL 4和p53之间的相互作用诱导受损的p53的再活化，导致细胞死亡。此外，裸鼠异种移植模型显示5-氮杂-CR依赖性L0 XL 4-p53轴减少肿瘤生长。在具有野生型p53肿瘤的肝癌患者中，观察到LOXL 4表达与总生存率之间的正相关性。总之，我们发现5-aza-CR诱导的LOXL 4上调重新激活野生型p53并触发细胞死亡，从而阻断肝癌的发展。
TP53 is the most frequently mutated gene in human cancer, whereas tumors with wild-type TP53 develop alternative strategies to survive. Identifying new regulators of p53 reactivation would greatly contribute to the development of cancer therapies. After screening the entire genome in liver cancer cells, we identified lysyl oxidase-like 4 (LOXL4) as a novel regulator for p53 activation. We found that 5-azacytidine (5-aza-CR) induces LOXL4 upregulation, with LOXL4 subsequently binding the basic domain of p53 via its low-isoelectric point region. The interaction between LOXL4 and p53 induces the reactivation of compromised p53, resulting in cell death. Furthermore, the nude mouse xenograft model showed that the 5-aza-CR-dependent LOXL4-p53 axis reduces tumor growth. A positive correlation between LOXL4 expression and overall survival in liver cancer patients with wild-type p53 tumors was observed. In conclusion, we found that 5-aza-CR-induced LOXL4 upregulation reactivates wild-type p53 and triggers cell death, which blocks liver cancer development.