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

Author:

Komini Chrysoula1,Theohari Irini2,Lambrianidou Andromachi1,Nakopoulou Lydia2,Trangas Theoni1ORCID

Affiliation:

1. Department of Biological Applications and Technology, University of Ioannina, Ioannina, 45110, Greece

2. First Department of Pathology, Medical School, University of Athens, Athens, 11517, Greece

Abstract

ABSTRACT 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 α (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.

Funder

State Scholarships Foundation

Publisher

The Company of Biologists

Subject

Cell Biology

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