Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma

被引：24

作者：

Singh, Shivendra ^{[1
]}

Abu-Zaid, Ahmed ^{[1
]}

Jin, Hongjian ^{[2
]}

Fang, Jie ^{[1
]}

Wu, Qiong ^{[1
]}

Wang, Tingting ^{[3
]}

Feng, Helin ^{[4
]}

Quarni, Waise ^{[1
]}

Shao, Ying ^{[5
]}

Maxham, Lily ^{[5
]}

Abdolvahabi, Alireza ^{[6
]}

Yun, Mi-Kyung ^{[7
]}

Vaithiyalingam, Sivaraja ^{[7
,8
]}

Tan, Haiyan ^{[7
,9
]}

Bowling, John ^{[6
]}

Honnell, Victoria ^{[10
]}

Young, Brandon ^{[6
]}

Guo, Yian ^{[11
]}

Bajpai, Richa ^{[12
]}

Pruett-Miller, Shondra M. ^{[12
]}

Grosveld, Gerard C. ^{[13
]}

Hatley, Mark ^{[14
]}

Xu, Beisi ^{[2
]}

Fan, Yiping ^{[2
]}

Wu, Gang ^{[2
]}

Chen, Eleanor Y. ^{[15
]}

Chen, Taosheng ^{[6
]}

Lewis, Peter W. ^{[16
]}

Rankovic, Zoran ^{[6
]}

Li, Yimei ^{[11
]}

Murphy, Andrew J. ^{[1
]}

Easton, John ^{[5
]}

Peng, Junmin ^{[7
,9
]}

Chen, Xiang ^{[5
]}

Wang, Ruoning ^{[3
]}

White, Stephen W. ^{[7
,10
]}

Davidoff, Andrew M. ^{[1
]}

Yang, Jun ^{[1
,10
,17
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Surg, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Ctr Appl Bioinformat, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[3] Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, Abigail Wexner Res Inst, 700 Childrens Dr, Columbus, OH 43205 USA

[4] Hebei Med Univ, Hosp 4, Dept Orthoped, Shijiazhuang 050011, Hebei, Peoples R China

[5] St Jude Childrens Res Hosp, Dept Computat Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Dept Struct Biol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[8] St Jude Childrens Res Hosp, Prot Technol Ctr, Mol Interact Anal, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[9] St Jude Childrens Res Hosp, Ctr Prote & Metabol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[10] St Jude Childrens Res Hosp, Grad Sch Biomed Sci, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[11] St Jude Childrens Res Hosp, Dept Biostat, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[12] St Jude Childrens Res Hosp, Ctr Adv Genome Engn, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[13] St Jude Childrens Res Hosp, Dept Genet, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[14] St Jude Childrens Res Hosp, Dept Oncol, 262 Danny Thomas Pl, Memphis, TN 38105 USA

[15] Univ Washington, Dept Lab Med & Pathol, Seattle, WA 98195 USA

[16] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomol Chem, Madison, WI 53706 USA

[17] Univ Tennessee, Hlth Sci Ctr, Coll Med, Dept Pathol, 930 Madison Ave,Suite 500, Memphis, TN 38163 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2022年 / 14卷 / 653期

关键词：

HISTONE DEMETHYLASE JMJD2B; CORE-REGULATORY CIRCUITRY; PAX3-FKHR FUSION PROTEIN; EMBRYONAL RHABDOMYOSARCOMA; TRANSCRIPTION FACTORS; SUPER-ENHANCERS; GENE; EXPRESSION; IDENTIFICATION; INHIBITION;

D O I：

10.1126/scitranslmed.abq2096

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1(+) RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1-governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1(+) RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1-related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.

引用

页数：17

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