Evaluation of Spliceosome Protein SmD2 as a Potential Target for Cancer Therapy.

Abstract

The core spliceosome Sm proteins are gaining attention as potential targets for cancer treatment. Here, we evaluate this, with focus on SmD2. A pan-cancer analysis including 26 solid tumor types revealed that the SmD2-encoding SNRPD2 gene was overexpressed in almost all cancers. In several cancers, high SNRPD2 expression was associated with a poor prognosis. To investigate the vulnerability of human cells to the loss of SmD2 expression, we silenced SNRPD2 using a short hairpin-expressing lentiviral vector in established cancer cell lines; in short-term cultured melanoma cells; and in several normal cell cultures, including cancer-associated fibroblasts cultured from non-small cell lung cancer resections. Additionally, we analyzed publicly available cell viability datasets for the dependency of cancer cell lines to SmD2 expression. Together, these studies clearly established SmD2 as a cancer-selective lethal target. Delving into genes with similar essentiality profiles to SNRPD2, we uncovered the intersected lethal stress between the loss of SmD2 and the loss of gene products participating in not only different mRNA processing steps including mRNA splicing, but also processes for coordinated protein production, as well as mitosis. Furthermore, we could correlate SNRPD2 expression to the responses of cancer cells to several FDA-approved anti-tumor drugs, especially to drugs inhibiting the cell cycle. Overall, our study confirms the anticipated role for targeting SmD2 in cancer treatment and reveals non-canonical SmD2 functions beyond mRNA splicing that could contribute to the dependency of cancer cells to high SNRPD2 expression.