N6-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression

被引：48

作者：

Chen, Pengxiang ^{[1
,2
]}

Li, Song ^{[2
,3
]}

Zhang, Ke ^{[4
]}

Zhao, Renchang ^{[5
]}

Cui, Jianfeng ^{[6
]}

Zhou, Wei ^{[1
]}

Liu, Yuchen ^{[1
]}

Zhang, Lin ^{[1
]}

Cheng, Yufeng ^{[1
]}

机构：

[1] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Radiat Oncol, Jinan, Peoples R China

[2] Shandong Univ, Cheeloo Coll Med, Qilu Hosp, Lab Basic Med Sci, Jinan, Peoples R China

[3] Shandong Univ, Cheeloo Coll Med, Qilu Hosp, Dept Med Oncol, Jinan, Peoples R China

[4] Shandong Univ, Cheeloo Coll Med, Qilu Hosp, Dept Gen Med, Jinan, Peoples R China

[5] Shandong Univ, Cheeloo Coll Med, Qilu Hosp, Thorac Surg Dept, Jinan, Peoples R China

[6] Shandong Univ, Cheeloo Coll Med, Qilu Hosp, Dept Urol, Jinan, Peoples R China

来源：

ONCOGENE | 2021年 / 40卷 / 37期

基金：

中国国家自然科学基金;

关键词：

UP-REGULATION; NUCLEAR-RNA; METASTASIS; PROLIFERATION; TRANSITION; CARCINOMA; CELLS; YAP;

D O I：

10.1038/s41388-021-01966-4

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：

N-6-Methyladenosine (m(6)A) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of m(6)A modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all m(6)A modifiers, ALKBH5 was the most potent member related to patient outcomes and suppressing esophageal cancer malignancy in cell and animal models. It demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an m(6)A/DGCR8-dependent manner. RAI1, previously considered as a circadian clock transcriptional regulator, was the main target of miR-194-2. It enhanced transcription of Hippo pathway upstream genes by binding to their 3 ' UTR and suppressed YAP/TAZ nuclear translocation. The ALKBH5/miR-194-2/RAI1 axis was also validated in clinical samples. In addition, the increased malignancy by low ALKBH5 was abolished by the YAP inhibitor verteporfin. Our findings uncover a critical role of ALKBH5 in miRNAs biogenesis and provide novel insight for developing treatment strategies in esophageal cancer.

引用

页码：5600 / 5612

页数：13

共 49 条

[1] N6-methyladenosine marks primary microRNAs for processing [J].

Alarcon, Claudio R. ;

Lee, Hyeseung ;

Goodarzi, Hani ;

Halberg, Nils ;

Tavazoie, Sohail F. .

NATURE, 2015, 519 (7544) :482-+

[2] Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations [J].

Barfield, Richard ;

Wang, Heming ;

Liu, Yongmei ;

Brody, Jennifer A. ;

Swenson, Brenton ;

Li, Ruitong ;

Bartz, Traci M. ;

Sotoodehnia, Nona ;

Chen, Yii-der I. ;

Cade, Brian E. ;

Chen, Han ;

Patel, Sanjay R. ;

Zhu, Xiaofeng ;

Gharib, Sina A. ;

Johnson, W. Craig ;

Rotter, Jerome I. ;

Saxena, Richa ;

Purcell, Shaun ;

Lin, Xihong ;

Redline, Susan ;

Sofer, Tamar .

SLEEP, 2019, 42 (08) :1-13

[3] m6A RNA Modification Controls Cell Fate Transition in Mammalian Embryonic Stem Cells [J].

Batista, Pedro J. ;

Molinie, Benoit ;

Wang, Jinkai ;

Qu, Kun ;

Zhang, Jiajing ;

Li, Lingjie ;

Bouley, Donna M. ;

Lujan, Ernesto ;

Haddad, Bahareh ;

Daneshvar, Kaveh ;

Carter, Ava C. ;

Flynn, Ryan A. ;

Zhou, Chan ;

Lim, Kok-Seong ;

Dedon, Peter ;

Wernig, Marius ;

Mullen, Alan C. ;

Xing, Yi ;

Giallourakis, Cosmas C. ;

Chang, Howard Y. .

CELL STEM CELL, 2014, 15 (06) :707-719

[4] Abnormal Circadian Rhythm of Melatonin in Smith-Magenis Syndrome Patients with RAI1 Point Mutations [J].

Boone, Philip M. ;

Reiter, Russel J. ;

Glaze, Daniel G. ;

Tan, Dun-Xian ;

Lupski, James R. ;

Potocki, Lorraine .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2011, 155A (08) :2024-2027

[5] Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men [J].

Chen, Han ;

Cade, Brian E. ;

Gleason, Kevin J. ;

Bjonnes, Andrew C. ;

Stilp, Adrienne M. ;

Sofer, Tamar ;

Conomos, Matthew P. ;

Ancoli-Israel, Sonia ;

Arens, Raanan ;

Azarbarzin, Ali ;

Bell, Graeme I. ;

Below, Jennifer E. ;

Chun, Sung ;

Evans, Daniel S. ;

Ewert, Ralf ;

Frazier-Wood, Alexis C. ;

Gharib, Sina A. ;

Haba-Rubio, Jose ;

Hagen, Erika W. ;

Heinzer, Raphael ;

Hillman, David R. ;

Johnson, W. Craig ;

Kutalik, Zoltan ;

Lane, Jacqueline M. ;

Larkin, Emma K. ;

Lee, Seung Ku ;

Liang, Jingjing ;

Loredo, Jose S. ;

Mukherjee, Sutapa ;

Palmer, Lyle J. ;

Papanicolaou, George J. ;

Penzel, Thomas ;

Peppard, Paul E. ;

Post, Wendy S. ;

Ramos, Alberto R. ;

Rice, Ken ;

Rotter, Jerome I. ;

Sands, Scott A. ;

Shah, Neomi A. ;

Shin, Chol ;

Stone, Katie L. ;

Stubbe, Beate ;

Sul, Jae Hoon ;

Tafti, Mehdi ;

Taylor, Kent D. ;

Teumer, Alexander ;

Thornton, Timothy A. ;

Tranah, Gregory J. ;

Wang, Chaolong ;

Wang, Heming .

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 2018, 58 (03) :391-401

[6] The role of m6A RNA methylation in human cancer [J].

Chen, Xiao-Yu ;

Zhang, Jing ;

Zhu, Jin-Shui .

MOLECULAR CANCER, 2019, 18 (1)

[7] ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1 [J].

Chen, Yunhao ;

Zhao, Yanchun ;

Chen, Junru ;

Peng, Chuanhui ;

Zhang, Yanpeng ;

Tong, Rongliang ;

Cheng, Qiyang ;

Yang, Beng ;

Feng, Xiaode ;

Lu, Yuejie ;

Xie, Haiyang ;

Zhou, Lin ;

Wu, Jian ;

Zheng, Shusen .

MOLECULAR CANCER, 2020, 19 (01)

[8] Causes and consequences of microRNA dysregulation in cancer [J].

Croce, Carlo M. .

NATURE REVIEWS GENETICS, 2009, 10 (10) :704-714

[9] Downregulation of YAP inhibits proliferation and induces apoptosis in Eca-109 cells [J].

Cui, Mu ;

Li, Zhen .

EXPERIMENTAL AND THERAPEUTIC MEDICINE, 2018, 15 (01) :1048-1052

[10] MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2 [J].

Das, Rajdeep ;

Gregory, Philip A. ;

Fernandes, Rayzel C. ;

Denis, Iza ;

Wang, Qingqing ;

Townley, Scott L. ;

Zhao, Shuang G. ;

Hanson, Adrienne R. ;

Pickering, Marie A. ;

Armstrong, Heather K. ;

Lokman, Noor A. ;

Ebrahimie, Esmaeil ;

Davicioni, Elai ;

Jenkins, Robert B. ;

Karnes, R. Jeffrey ;

Ross, Ashley E. ;

Den, Robert B. ;

Klein, Eric A. ;

Chi, Kim N. ;

Ramshaw, Hayley S. ;

Williams, Elizabeth D. ;

Zoubeidi, Amina ;

Goodall, Gregory J. ;

Feng, Felix Y. ;

Butler, Lisa M. ;

Tilley, Wayne D. ;

Selth, Luke A. .

CANCER RESEARCH, 2017, 77 (04) :1021-1034

← 1 2 3 4 5 →