TY - JOUR
T1 - PELP1 oncogenic functions involve alternative splicing via PRMT6
AU - Mann, Monica
AU - Zou, Yi
AU - Chen, Yidong
AU - Brann, Darrell
AU - Vadlamudi, Ratna
N1 - Funding Information:
We thank Dr. Sujit Nair for the confocal assay and the CD44 minigene assay. We thank Dr. Rakesh Kumar for the ERE-CD44 minigene plasmid. We thank Lai Zhao and Dawn Garcia at the Next Generation Sequencing Core for the RNA sequencing. The confocal images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA , NIH - NCI P30 CA54174 (CTRC at UTHSCSA) and NIH- NIA P01AG19316 . This research was funded by the NIH CA095681 and NIH 1 F31 CA173909-01A1 .
PY - 2014/3
Y1 - 2014/3
N2 - Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a proto-oncogene that functions as coactivator of the estrogen receptor and is an independent prognostic predictor of shorter survival of breast cancer patients. The dysregulation of PELP1 in breast cancer has been implicated in oncogenesis, metastasis, and therapy resistance. Although several aspects of PELP1 have been studied, a complete list of PELP1 target genes remains unknown, and the molecular mechanisms of PELP1 mediated oncogenesis remain elusive. In this study, we have performed a whole genome analysis to profile the PELP1 transcriptome by RNA-sequencing and identified 318 genes as PELP1 regulated genes. Pathway analysis revealed that PELP1 modulates several pathways including the molecular mechanisms of cancer, estrogen signaling, and breast cancer progression. Interestingly, RNA-seq analysis also revealed that PELP1 regulates the expression of several genes involved in alternative splicing. Accordingly, the PELP1 regulated genome includes several uniquely spliced isoforms. Mechanistic studies show that PELP1 binds RNA with a preference to poly-C, co-localizes with the splicing factor SC35 at nuclear speckles, and participates in alternative splicing. Further, PELP1 interacts with the arginine methyltransferase PRMT6 and modifies PRMT6 functions. Inhibition of PRMT6 reduced PELP1-mediated estrogen receptor activation, cellular proliferation, and colony formation. PELP1 and PRMT6 are co-recruited to estrogen receptor target genes, PELP1 knockdown affects the enrichment of histone H3R2 di-methylation, and PELP1 and PRMT6 coordinate to regulate the alternative splicing of genes involved in cancer. Collectively, our data suggest that PELP1 oncogenic functions involve alternative splicing leading to the activation of unique pathways that support tumor progression and that the PELP1-PRMT6 axis may be a potential target for breast cancer therapy.
AB - Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a proto-oncogene that functions as coactivator of the estrogen receptor and is an independent prognostic predictor of shorter survival of breast cancer patients. The dysregulation of PELP1 in breast cancer has been implicated in oncogenesis, metastasis, and therapy resistance. Although several aspects of PELP1 have been studied, a complete list of PELP1 target genes remains unknown, and the molecular mechanisms of PELP1 mediated oncogenesis remain elusive. In this study, we have performed a whole genome analysis to profile the PELP1 transcriptome by RNA-sequencing and identified 318 genes as PELP1 regulated genes. Pathway analysis revealed that PELP1 modulates several pathways including the molecular mechanisms of cancer, estrogen signaling, and breast cancer progression. Interestingly, RNA-seq analysis also revealed that PELP1 regulates the expression of several genes involved in alternative splicing. Accordingly, the PELP1 regulated genome includes several uniquely spliced isoforms. Mechanistic studies show that PELP1 binds RNA with a preference to poly-C, co-localizes with the splicing factor SC35 at nuclear speckles, and participates in alternative splicing. Further, PELP1 interacts with the arginine methyltransferase PRMT6 and modifies PRMT6 functions. Inhibition of PRMT6 reduced PELP1-mediated estrogen receptor activation, cellular proliferation, and colony formation. PELP1 and PRMT6 are co-recruited to estrogen receptor target genes, PELP1 knockdown affects the enrichment of histone H3R2 di-methylation, and PELP1 and PRMT6 coordinate to regulate the alternative splicing of genes involved in cancer. Collectively, our data suggest that PELP1 oncogenic functions involve alternative splicing leading to the activation of unique pathways that support tumor progression and that the PELP1-PRMT6 axis may be a potential target for breast cancer therapy.
KW - Alternative splicing
KW - Breast cancer
KW - Epigenetics
KW - PELP1
KW - PRMT6
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U2 - 10.1016/j.molonc.2013.12.012
DO - 10.1016/j.molonc.2013.12.012
M3 - Article
C2 - 24447537
AN - SCOPUS:84894324359
SN - 1574-7891
VL - 8
SP - 389
EP - 400
JO - Molecular oncology
JF - Molecular oncology
IS - 2
ER -