PAPOLA contributes to cyclin D1 mRNA alternative polyadenylation and promotes breast cancer cell proliferation

Poly(A) polymerases add the poly(A) tail at the 3 ' end of nearly all eukaryotic mRNA, and are associated with proliferation and cancer. To elucidate the role of the most-studied mammalian poly(A) polymerase, poly(A) polymerase alpha (PAPOLA), in cancer, we assessed its expression in 221 breast cancer samples and found it to correlate strongly with the aggressive triple-negative subtype. Silencing PAPOLA in MCF-7 and MDA-MB-231 breast cancer cells reduced proliferation and anchorage-independent growth by decreasing steady-state cyclin D1 (CCND1) mRNA and protein levels. Whereas the length of the CCND1 mRNA poly(A) tail was not affected, its 3 ' untranslated region (3 ' UTR) lengthened. Overexpressing PAPOLA caused CCND1 mRNA 3 ' UTR shortening with a concomitant increase in the amount of corresponding transcript and protein, resulting in growth arrest in MCF-7 cells and DNA damage in HEK-293 cells. Such overexpression of PAPOLA promoted proliferation in the p53 mutant MDA-MB-231 cells. Our data suggest that PAPOLA is a possible candidate target for the control of tumor growth that is mostly relevant to triple-negative tumors, a group characterized by PAPOLA overexpression and lack of alternative targeted therapies.

Automated summary

Poly(A) polymerases add poly(A) tail to most eukaryotic mRNA, and are linked to proliferation and cancer. Research on breast cancer samples revealed that overexpression of PAPOLA is associated with aggressive triple-negative subtype, impacting cell proliferation and growth through modulation of CCND1 mRNA 3' UTR length.