Inhibiting an RBM39/MLL1 epigenomic regulatory complex with dominant-negative peptides disrupts cancer cell transcription and proliferation

被引：15

作者：

Puvvula, Pavan Kumar ^{[1
]}

Yu, Yao ^{[2
]}

Sullivan, Kaelan Renaldo ^{[1
]}

Eyob, Henok ^{[3
]}

Rosenberg, Julian ^{[1
]}

Welm, Alana ^{[3
]}

Huff, Chad ^{[2
]}

Moon, Anne M. ^{[1
,4
]}

机构：

[1] Weis Ctr Res, Geisinger Clin, Dept Mol & Funct Genom, Danville, PA 17822 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA

[3] Univ Utah, Dept Oncol Sci, Salt Lake City, UT USA

[4] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA

来源：

CELL REPORTS | 2021年 / 35卷 / 09期

关键词：

H3; LYSINE; 4; PROTEIN INTERACTIONS; GENE-REGULATION; CAPER-ALPHA; MLL FAMILY; CHROMATIN; EXPRESSION; GROWTH; TRIMETHYLATION; METHYLATION;

D O I：

10.1016/j.celrep.2021.109156

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

RBM39 is a known splicing factor and coactivator. Here, we report that RBM39 functions as a master transcriptional regulator that interacts with the MLL1 complex to facilitate chromatin binding and H3K4 trimethylation in breast cancer cells. We identify RBM39 functional domains required for DNA and complex binding and show that the loss of RBM39 has widespread effects on H3K4me3 and gene expression, including key oncogenic pathways. RBM39's RNA recognition motif 3 (RRM3) functions as a dominant-negative domain; namely, it disrupts the complex and H3K4me trimethylation and expression of RBM/MLL1 target genes. RRM3-derived cell-penetrating peptides phenocopy the effects of the loss of RBM39 to decrease growth and survival of all major subtypes of breast cancer and yet are nontoxic to normal cells. These findings establish RBM39/MLL1 as a major contributor to the abnormal epigenetic landscape in breast cancer and lay the foundation for peptide-mediated cancer-specific therapy based on disruption of RBM39 epigenomic functions.

引用

页数：26