Abstract
ABSTRACTStar-PAP, a nuclear phosphatidylinositol (PI) signal-regulated poly(A) polymerase (PAP), couples with type I PI phosphate kinase α (PIPKIα) and controls gene expression. We show that Star-PAP and PIPKIα together regulate 3′-end processing and expression of pre-mRNAs encoding key anti-invasive factors (KISS1R, CDH1, NME1, CDH13, FEZ1, and WIF1) in breast cancer. Consistently, the endogenous Star-PAP level is negatively correlated with the cellular invasiveness of breast cancer cells. While silencing Star-PAP or PIPKIα increases cellular invasiveness in low-invasiveness MCF7 cells, Star-PAP overexpression decreases invasiveness in highly invasive MDA-MB-231 cells in a cellular Star-PAP level-dependent manner. However, expression of the PIPKIα-noninteracting Star-PAP mutant or the phosphodeficient Star-PAP (S6A mutant) has no effect on cellular invasiveness. These results strongly indicate that PIPKIα interaction and Star-PAP S6 phosphorylation are required for Star-PAP-mediated regulation of cancer cell invasion and give specificity to target anti-invasive gene expression. Our study establishes Star-PAP–PIPKIα-mediated 3′-end processing as a key anti-invasive mechanism in breast cancer.
Highlights
Star-Poly(A) polymerases (PAPs), a nuclear phosphatidylinositol (PI) signal-regulated poly(A) polymerase (PAP), couples with type I PI phosphate kinase ␣ (PIPKI␣) and controls gene expression
We previously showed the direct interaction of Star-PAP with PIPKI␣ and that it occurred in the ZF region at the Star-PAP N terminus [20]
Serine 6-to-alanine (S6A) mutation abolished the association between Star-PAP and PIPKI␣ [20]
Summary
Star-PAP, a nuclear phosphatidylinositol (PI) signal-regulated poly(A) polymerase (PAP), couples with type I PI phosphate kinase ␣ (PIPKI␣) and controls gene expression. We show that Star-PAP and PIPKI␣ together regulate 3=-end processing and expression of pre-mRNAs encoding key anti-invasive factors (KISS1R, CDH1, NME1, CDH13, FEZ1, and WIF1) in breast cancer. Expression of the PIPKI␣noninteracting Star-PAP mutant or the phosphodeficient Star-PAP (S6A mutant) has no effect on cellular invasiveness These results strongly indicate that PIPKI␣ interaction and Star-PAP S6 phosphorylation are required for Star-PAP-mediated regulation of cancer cell invasion and give specificity to target anti-invasive gene expression. Microarray analysis after Star-PAP knockdown suggests that multiple cellular functions and signaling pathways are regulated by Star-PAP [17], yet the role of Star-PAP in cell invasion/migration is still undefined. Star-PAP interacts with and is regulated by the nuclear type I phosphatidylinositol (PI) phosphate kinase I␣ (PIPKI␣), which synthesizes nuclear PI4,5P2 [17, 20]
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