PUS7-dependent pseudouridylation of ALKBH3 mRNA inhibits gastric cancer progression

被引：12

作者：

Chang, Yongxia ^{[1
,2
]}

Jin, Hao ^{[1
,2
]}

Cui, Yun ^{[1
,2
]}

Yang, Feng ^{[3
]}

Chen, Kanghua ^{[2
]}

Kuang, Wenjun ^{[4
]}

Huo, Chunxiao ^{[2
]}

Xu, Zhangqi ^{[1
]}

Li, Ya ^{[1
]}

Lin, Aifu ^{[5
]}

Yang, Bo ^{[6
,7
]}

Liu, Wei ^{[8
,9
]}

Xie, Shanshan ^{[1
]}

Zhou, Tianhua ^{[2
,10
]}

机构：

[1] Zhejiang Univ, Sch Med, Childrens Hosp, Natl Clin Res Ctr Child Hlth, Hangzhou, Zhejiang, Peoples R China

[2] Zhejiang Univ, Sch Med, Dept Cell Biol, Hangzhou, Zhejiang, Peoples R China

[3] Zhejiang Univ, Binjiang Inst, Hangzhou, Zhejiang, Peoples R China

[4] Zhejiang Univ, Int Inst Med, Sch Med, Affiliated Hosp 4, Yiwu, Zhejiang, Peoples R China

[5] Zhejiang Univ, Coll Life Sci, MOE Lab Biosyst Homeostasis & Protect, Hangzhou, Zhejiang, Peoples R China

[6] Zhejiang Univ, Inst Pharmacol & Toxicol, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou, Zhejiang, Peoples R China

[7] Hangzhou City Univ, Sch Med, Hangzhou, Zhejiang, Peoples R China

[8] Zhejiang Univ, Int Inst Med, Sch Med, Metab Med Ctr, Yiwu, Zhejiang, Peoples R China

[9] Zhejiang Univ, Affiliated Hosp 4, Sch Med, Yiwu, Zhejiang, Peoples R China

[10] Zhejiang Univ, Canc Ctr, Hangzhou, Zhejiang, Peoples R China

来源：

CLINICAL AND TRANSLATIONAL MEDICINE | 2024年 / 14卷 / 08期

基金：

中国国家自然科学基金;

关键词：

alkbh3; gastric cancer; pseudouridylation; pus7;

D O I：

10.1002/ctm2.1811

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: RNA pseudouridylation is a critical post-transcriptional modification that influences gene expression and impacts various biological functions. Despite its significance, the role of mRNA pseudouridylation in cancer remains poorly understood. This study investigates the impact of pseudouridine synthase 7 (PUS7)-mediated pseudouridylation of Alpha-ketoglutarate-dependent Dioxygenase alkB Homolog 3 (ALKBH3) mRNA in gastric cancer. Methods: Immunohistochemistry and Western blotting were used to assess PUS7 protein levels in human gastric cancer tissues. The relationship between PUS7 and gastric cancer progression was examined using 3D colony formation assays and subcutaneous xenograft models. Real-time quantitative PCR (RT-qPCR), Western blotting, and polysome profiling assays were conducted to investigate how PUS7 regulates ALKBH3. A locus-specific pseudouridine (Psi) detection assay was used to identify Psi sites on ALKBH3 mRNA. Results: Our findings indicate a significant reduction of PUS7 in gastric cancer tissues compared to adjacent non-tumour tissues. Functional analyses reveal that PUS7 inhibits gastric cancer cell proliferation and tumour growth via its catalytic activity. Additionally, PUS7 enhances the translation efficiency of ALKBH3 mRNA by modifying the U696 site with pseudouridine, thereby attenuating tumour growth. Importantly, ALKBH3 functions as a tumour suppressor in gastric cancer, with its expression closely correlated with PUS7 levels in tumour tissues. Conclusions: PUS7-dependent pseudouridylation of ALKBH3 mRNA enhances its translation, thereby suppressing gastric cancer progression. These findings highlight the potential significance of mRNA pseudouridylation in cancer biology and suggest a therapeutic target for gastric cancer.

引用

页数：18

共 35 条

[1] Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA [J].

Aas, PA ;

Otterlei, M ;

Falnes, PO ;

Vågbo, CB ;

Skorpen, F ;

Akbari, M ;

Sundheim, O ;

Bjorås, M ;

Slupphaug, G ;

Seeberg, E ;

Krokan, HE .

NATURE, 2003, 421 (6925) :859-863

[2] Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation [J].

Anderson, Bart R. ;

Muramatsu, Hiromi ;

Nallagatla, Subba R. ;

Bevilacqua, Philip C. ;

Sansing, Lauren H. ;

Weissman, Drew ;

Kariko, Katalin .

NUCLEIC ACIDS RESEARCH, 2010, 38 (17) :5884-5892

[3] Regulation and Function of RNA Pseudouridylation in Human Cells [J].

Borchardt, Erin K. ;

Martinez, Nicole M. ;

Gilbert, Wendy V. .

ANNUAL REVIEW OF GENETICS, VOL 54, 2020, 2020, 54 :309-336

[4] mRNA structure determines modification by pseudouridine synthase 1 [J].

Carlile, Thomas M. ;

Martinez, Nicole M. ;

Schaening, Cassandra ;

Su, Amanda ;

Bell, Tristan A. ;

Zinshteyn, Boris ;

Gilbert, Wendy, V .

NATURE CHEMICAL BIOLOGY, 2019, 15 (10) :966-+

[5]

Carlile Thomas M, 2015, Curr Protoc Mol Biol, V112, DOI [10.1002/0471142727.mb0425s112, 10.1002/0471142727.mb0425s112]

[6] Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells [J].

Carlile, Thomas M. ;

Rojas-Duran, Maria F. ;

Zinshteyn, Boris ;

Shin, Hakyung ;

Bartoli, Kristen M. ;

Gilbert, Wendy V. .

NATURE, 2014, 515 (7525) :143-+

[7] Decoding pseudouridine: an emerging target for therapeutic development [J].

Cerneckis, Jonas ;

Cui, Qi ;

He, Chuan ;

Yi, Chengqi ;

Shi, Yanhong .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2022, 43 (06) :522-535

[8] Analysis of translation using polysome profiling [J].

Chasse, Heloise ;

Boulben, Sandrine ;

Costache, Vlad ;

Cormier, Patrick ;

Morales, Julia .

NUCLEIC ACIDS RESEARCH, 2017, 45 (03) :e15

[9] Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs [J].

Chen, Zhuojia ;

Qi, Meijie ;

Shen, Bin ;

Luo, Guanzheng ;

Wu, Yingmin ;

Li, Jiexin ;

Lu, Zhike ;

Zheng, Zhong ;

Dai, Qing ;

Wang, Hongsheng .

NUCLEIC ACIDS RESEARCH, 2019, 47 (05) :2533-2545

[10] Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis [J].

Cui, Qi ;

Yin, Kailin ;

Zhang, Xiaoting ;

Ye, Peng ;

Chen, Xianwei ;

Chao, Jianfei ;

Meng, Haowei ;

Wei, Jiangbo ;

Roeth, Daniel ;

Li, Li ;

Qin, Yue ;

Sun, Guihua ;

Zhang, Mingzi ;

Klein, Jeremy ;

Huynhle, Marvin ;

Wang, Cheng ;

Zhang, Leying ;

Badie, Behnam ;

Kalkum, Markus ;

He, Chuan ;

Yi, Chengqi ;

Shi, Yanhong .

NATURE CANCER, 2021, 2 (09) :932-+

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