Abstract
The oncogene LSF has been proposed as a novel target with therapeutic potential for multiple cancers. LSF overexpression correlates with poor prognosis for both liver and colorectal cancers, for which there are currently limited therapeutic treatment options. In particular, molecularly targeted therapies for hepatocellular carcinoma targeting cellular receptors and kinases have yielded disappointing clinical results, providing an urgency for targeting distinct mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models of hepatocellular carcinoma, with no observable toxicity. To understand how the inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Phenotypically, inhibition of LSF activity induced a mitotic delay with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. The cellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA specifically targeting LSF produced nearly identical phenotypes. Taken together, these findings confirm that LSF is a promising therapeutic target for cancer treatment.
Significance Specific inhibition of LSF by either small molecules or siRNA results in mitotic defects resulting in cell death or senescence, supporting the promise for LSF inhibitory strategies as treatment for LSF-related cancers with high unmet medical needs.
Footnotes
Financial Support: The research was supported by: Alnylam Pharmaceuticals, Inc (JLSW, KF), Boston University (JLSW, UH, SES), BU Undergraduate Research Opportunity (MR), New England Biolabs, Inc. (HGC), and the NIH (R01 GM078240) to SES.
Conflict of Interest Disclosure: SES and UH are co-founders of Lamerigen, Inc. JLSW and KF are employed by Alnylam Pharmaceuticals. The remaining authors declare no potential conflict of interest.