We previously mapped a 5.5 kb homozygous deletion in cervical cancer cell lines and primary tumors to chromosome 11q13 within the 1st intron of PACS-1 gene, which encodes a membrane traffic regulator. This deletion correlates with elevated expression of 120 kDa PACS-1 in primary cervical tumors compared to normal tissues as well as the expression of a 140 kDa immunoreactive isoform in the nucleus specifically in cervical cancer cell lines. Inspection of the PACS-1 mRNA sequence revealed a target site for miR449a, which mediates cell fate. Northern blot analysis showed miRNA 449a expression was reduced in cervical cancer cell lines and primary tumors suggesting that dysregulation of miRNA449a or the intronic deletion contributed to aberrant PACS-1 expression and that the increased expression of PACS-1 may mediate cell viability and cell cycle progression. Consistent with this possibility, siRNA knockdown of PACS-1 or increased expression of miR449a caused cells to accumulate in S phase and induced expression of γH2AX. By contrast, overexpression of PACS-1 or expression of antimiR 449a reduced γH2AX expression. Whereas PACS-1 mediates secretory pathway trafficking, the effect of PACS-1 expression on genome stability suggested PACS-1 might shuttle between the cytoplasm and the nucleus to mediate genome stability. Consistent with this possibility, the PACS-1 sequence contains canonical NLS and NES motifs. Indeed, confocal microscopy studies revealed GFP-tagged PACS-1 accumulated in the nucleus in a leptomycin B-dependent manner. We hypothesize that aberrant expression of PACS-1 in cervical cancer cells results in the stabilization and replication of rearranged DNA sequences leading to tumor development.

Citation Format: Mysore S. Veena, Saroj K. Basak, Natarajan Venkatesan, Alborz Zinabadi, Laurel Thomas, Gary Thomas, Eri S. Srivatsan. The membrane traffic regulator PACS-1 mediates genome stability at S-phase of the cell cycle. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5187. doi:10.1158/1538-7445.AM2013-5187