The DNMT1-PAS1-PH20 axis drives breast cancer growth and metastasis

被引：41

作者：

Fu, Yenan ^{[1
,2
,3
]}

Zhang, Xi ^{[1
,2
,3
]}

Liu, Xiao ^{[4
]}

Wang, Peng ^{[1
,2
,3
]}

Chu, Wenhui ^{[1
,2
,3
]}

Zhao, Wei ^{[1
,2
,3
]}

Wang, Yunling ^{[5
]}

Zhou, Guangbiao ^{[6
]}

Yu, Yu ^{[1
,2
,3
]}

Zhang, Hongquan ^{[1
,2
,3
]}

机构：

[1] Peking Univ Hlth Sci Ctr, Program Canc & Cell Biol, Dept Human Anat Histol & Embryol, Sch Basic Med Sci,PKU Int Canc Inst, Beijing 100191, Peoples R China

[2] Peking Univ Hlth Sci Ctr, MOE Key Lab Carcinogenesis & Translat Res, Beijing 100191, Peoples R China

[3] Peking Univ Hlth Sci Ctr, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

[4] Peking Univ Third Hosp, Dept Orthoped, Beijing 100191, Peoples R China

[5] Peking Univ, Inst Cardiovasc Res, Beijing 100191, Peoples R China

[6] Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Natl Clin Res Ctr Canc, State Key Lab Mol Oncol,Natl Canc Ctr, Beijing 100021, Peoples R China

来源：

SIGNAL TRANSDUCTION AND TARGETED THERAPY | 2022年 / 7卷 / 01期

基金：

中国国家自然科学基金;

关键词：

DNA METHYLATION; HYALURONIDASE; BINDING; PH-20; EXPRESSION; INHIBITORS; MECHANISM; CARCINOMA; PATHWAY;

D O I：

10.1038/s41392-022-00896-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

PH20 is a member of the human hyaluronidase family that degrades hyaluronan in the extracellular matrix and controls tumor progression. Inhibition of DNA methyltransferases (DNMTs) leads to elevated hyaluronan levels; however, whether DNMT inhibitors control PH20 remains unclear. Here, we report that the DNMT1 inhibitor, decitabine, suppresses PH20 expression by activating the long non-coding RNA PHACTR2-AS1 (PAS1). PAS1 forms a tripartite complex with the RNA-binding protein vigilin and histone methyltransferase SUV39H1. The interaction between PAS1 and vigilin maintains the stability of PAS1. Meanwhile, PAS1 recruits SUV39H1 to trigger the H3K9 methylation of PH20, resulting in its silencing. Functionally, PAS1 inhibits breast cancer growth and metastasis, at least partially, by suppressing PH20. Combination therapy of decitabine and PAS1-30nt-RNA, which directly binds to SUV39H1, effectively blocked breast cancer growth and metastasis in mice. Taken together, DNMT1, PAS1, and PH20 comprise a regulatory axis to control breast cancer growth and metastasis. These findings reveal that the DNMT1-PAS1-PH20 axis is a potential therapeutic target for breast cancer.

引用

页数：11

共 38 条

[11] Vigilin binding selectively inhibits cleavage of the vitellogenin mRNA 3′-untranslated region by the mRNA endonuclease polysomal ribonuclease 1 [J].