RBM4-Regulated Alternative Splicing Suppresses Tumorigenesis

Dysregulation of alternative splicing has been implicated in tumor progression, but the mechanisms by which changes in the expression and activity of splicing factors promote tumorigenesis are not completely understood. The oncogenic splicing factor serine/arginine–rich splicing factor 1 (SRSF1) has been shown to modulate the splicing of many cancer-associated genes, including those that activate the mTOR pathway. Wang and colleagues investigated the role of another splicing factor, RNA-binding motif protein 4 (RBM4), in the regulation of alternative splicing and tumor progression. RBM4 suppressed various alternative splicing events in a sequence-specific manner via direct binding to pre-mRNA and negatively regulated the splicing of many cancer-associated genes, such as those involved in proliferation, cell migration, and apoptosis. RBM4 expression inhibited cancer cell proliferation and migration and impaired xenograft tumor growth in vivo, suggesting that RBM4 functions as a tumor suppressor. Consistent with this idea, RBM4 stimulated cancer cell apoptosis by inducing a shift in the alternative splicing of BCL2-like 1 (BCL2L1, also known as BCL-X), resulting in increased expression of the proapoptotic BCL-XS isoform and decreased expression of the antiapoptotic BCL-XL isoform. The tumor-suppressive effects of RBM4 were mediated in part by BCL-X splicing, as concomitant expression of BCL-XL partially restored lung cancer cell proliferation and migration and enhanced xenograft tumor growth. In addition, RBM4 specifically reduced the expression of SRSF1 and antagonized its oncogenic activity via competitive binding to similar cis-elements in pre-mRNAs; coexpression of RBM4 prevented the oncogenic splicing of several SRSF1-regulated genes, including BCL-XL, and inhibited SRSF1-driven mTOR activation. RBM4 expression was decreased in human non–small cell lung cancer samples with increased BCL-XL, and elevated RBM4 expression correlated with prolonged survival in several cancer types. These findings identify RBM4 as a tumor-suppressive splicing factor and suggest that restoration of RBM4 expression may limit tumor growth and progression.

Wang Y, Chen D, Qian H, Tsai YS, Shao S, Liu Q, et al. The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell 2014;26:374–89.

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