BET inhibitor suppresses migration of human hepatocellular carcinoma by inhibiting SMARCA4

被引：25

作者：

Choi, Hae In ^{[1
]}

An, Ga Yeong ^{[1
]}

Baek, Mina ^{[2
,3
]}

Yoo, Eunyoung ^{[1
]}

Chai, Jin Choul ^{[4
]}

Lee, Young Seek ^{[4
]}

Jung, Kyoung Hwa ^{[5
,6
]}

Chai, Young Gyu ^{[1
,3
]}

机构：

[1] Hanyang Univ, Dept Bionanotechnol, Seoul 04673, South Korea

[2] Hanyang Univ, Inst Nat Sci & Technol, Ansan 15588, South Korea

[3] Hanyang Univ, Dept Mol & Life Sci, Ansan 15588, South Korea

[4] Seoul Natl Univ, Coll Vet Med, Seoul 08826, South Korea

[5] Convergence Technol Campus Korea Polytech II, Incheon 21417, South Korea

[6] Gwangmyeong Convergence Technol Campus Korea Poly, Dept Biopharmaceut Syst, Gwangmyeong 14222, South Korea

来源：

SCIENTIFIC REPORTS | 2021年 / 11卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

CELL-PROLIFERATION; UP-REGULATION; BRD4; EPIREGULIN; GROWTH; RNA; METASTASES; COMPLEXES; TARGETS; READERS;

D O I：

10.1038/s41598-021-91284-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Hepatocellular carcinoma (HCC) is one of the most prevalent and poorly responsive cancers worldwide. Bromodomain and extraterminal (BET) inhibitors, such as JQ1 and OTX-015, inhibit BET protein binding to acetylated residues in histones. However, the physiological mechanisms and regulatory processes of BET inhibition in HCC remain unclear. To explore BET inhibitors' potential role in the molecular mechanisms underlying their anticancer effects in HCC, we analyzed BET inhibitor-treated HCC cells' gene expression profiles with RNA-seq and bioinformatics analysis. BET inhibitor treatment significantly downregulated genes related to bromodomain-containing proteins 4 (BRD4), such as ACSL5, SLC38A5, and ICAM2. Importantly, some cell migration-related genes, including AOC3, CCR6, SSTR5, and SCL7A11, were significantly downregulated. Additionally, bioinformatics analysis using Ingenuity Knowledge Base Ingenuity Pathway Analysis (IPA) revealed that SMARCA4 regulated migration response molecules. Furthermore, knockdown of SMARCA4 gene expression by siRNA treatment significantly reduced cell migration and the expression of migration-related genes. In summary, our results indicated that BET inhibitor treatment in HCC cell lines reduces cell migration through the downregulation of SMARCA4.

引用

页数：13

共 71 条

[1] Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival [J].

Abdel-Rahman, Omar ;

Lamarca, Angela .

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY, 2017, 11 (01) :75-83

[2] Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy [J].

Alqahtani, Ali ;

Choucair, Khalil ;

Ashraf, Mushtaq ;

Hammouda, Danae M. ;

Alloghbi, Abduraham ;

Khan, Talal ;

Senzer, Neil ;

Nemunaitis, John .

FUTURE SCIENCE OA, 2019, 5 (03)

[3] Hepatocellular carcinoma: a review [J].

Balogh, Julius ;

Victor, David, III ;

Asham, Emad H. ;

Burroughs, Sherilyn Gordon ;

Boktour, Maha ;

Saharia, Ashish ;

Li, Xian ;

Ghobrial, R. Mark ;

Monsour, Howard P., Jr. .

JOURNAL OF HEPATOCELLULAR CARCINOMA, 2016, 3 :41-53

[4] BET domain co-regulators in obesity, inflammation and cancer [J].

Belkina, Anna C. ;

Denis, Gerald V. .

NATURE REVIEWS CANCER, 2012, 12 (07) :465-477

[5] Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study [J].

Berthon, Celine ;

Raffoux, Emmanuel ;

Thomas, Xavier ;

Vey, Norbert ;

Gomez-Roca, Carlos ;

Yee, Karen ;

Taussig, David Christopher ;

Rezai, Keyvan ;

Roumier, Christophe ;

Herait, Patrice ;

Kahatt, Carmen ;

Quesnel, Bruno ;

Michallet, Mauricette ;

Recher, Christian ;

Lokiec, Francois ;

Preudhomme, Claude ;

Dombret, Herve .

LANCET HAEMATOLOGY, 2016, 3 (04) :E186-E195

[6] Trimmomatic: a flexible trimmer for Illumina sequence data [J].

Bolger, Anthony M. ;

Lohse, Marc ;

Usadel, Bjoern .

BIOINFORMATICS, 2014, 30 (15) :2114-2120

[7] Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance [J].

Buscarlet, Manuel ;

Krasteva, Veneta ;

Ho, Lena ;

Simon, Camille ;

Hebert, Josee ;

Wilhelm, Brian ;

Crabtree, Gerald R. ;

Sauvageau, Guy ;

Thibault, Pierre ;

Lessard, Julie A. .

BLOOD, 2014, 123 (11) :1720-1728

[8] Hepatic SMARCA4 predicts HCC recurrence and promotes tumour cell proliferation by regulating SMAD6 expression [J].

Chen, Zhiao ;

Lu, Xinyuan ;

Jia, Deshui ;

Jing, Ying ;

Chen, Di ;

Wang, Qifeng ;

Zhao, Fangyu ;

Li, Jinjun ;

Yao, Ming ;

Cong, Wenming ;

He, Xianghuo .

CELL DEATH & DISEASE, 2018, 9

[9] Bromodomains: a new target class for drug development [J].

Cochran, Andrea G. ;

Conery, Andrew R. ;

Sims, Robert J., III .

NATURE REVIEWS DRUG DISCOVERY, 2019, 18 (08) :609-628

[10] BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells [J].

Coude, Marie-Magdelaine ;

Braun, Thorsten ;

Berrou, Jeannig ;

Dupont, Melanie ;

Bertrand, Sibyl ;

Masse, Aline ;

Raffoux, Emmanuel ;

Itzykson, Raphael ;

Delord, Marc ;

Riveiro, Maria E. ;

Herait, Patrice ;

Baruchel, Andre ;

Dombret, Herve ;

Gardin, Claude .

ONCOTARGET, 2015, 6 (19) :17698-17712

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