Abstract
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.
Highlights
Cancer cells are generally resistant to programed cell death [1]
We found that loss of lysyl oxidase-like 4 (LOXL4) reduced the induction of cell death under 5-aza-CR treatment in SK-Hep1 and HepG2 cells, but not in Hep3B and Huh 7 cells (Fig. 1f)
Our findings suggest that overexpressed LOXL4 interacts with WT p53 which is required for promoted cell death
Summary
Cancer cells are generally resistant to programed cell death [1]. During carcinogenesis, they develop an adequate program to escape cell cycle control. p53 is a master regulator of cell cycle and is highly mutated in different cancer types. There are over 780,000 new liver cancer cases and approximately 740,000 deaths worldwide every year [6]. Discovery of novel strategies and drug targets for liver cancer treatment is urgent. A few studies have suggested that it promotes tumor proliferation and/or metastasis in head and neck squamous cell carcinoma and gastric cancer [15, 16]. In bladder and breast cancer, LOXL4 might function as a tumor suppressor because its loss promotes cancer cell proliferation and metastasis [16, 17]. We found that LOXL4 is a novel regulator that contributes to p53 activation in liver cancer. Our results illustrate that 5-azacytidinedependent LOXL4 derepression functionally contributes to the activation of compromised p53, which offers a promising therapeutic strategy for liver cancer
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