PT  - JOURNAL ARTICLE
AU  - Jennifer L.S. Willoughby
AU  - Kelly George
AU  - Mark P. Roberto
AU  - Hang Gyeong Chin
AU  - Patrick Stoiber
AU  - Hyunjin Shin
AU  - Chandra Sekhar Pedamallu
AU  - Scott E. Schaus
AU  - Kevin Fitzgerald
AU  - Jagesh Shah
AU  - Ulla Hansen
TI  - Targeting the oncogene LSF with either the small molecule inhibitor FQI1 or siRNA causes mitotic delays with unaligned chromosomes, resulting in cell death or senescence
AID  - 10.1101/665570
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 665570
4099  - http://biorxiv.org/content/early/2020/01/26/665570.short
4100  - http://biorxiv.org/content/early/2020/01/26/665570.full
AB  - Background The oncogene LSF (encoded by TFCP2) has been proposed as a novel therapeutic target for multiple cancers. LSF overexpression in patient tumors correlates with poor prognosis in particular for both hepatocellular carcinoma and colorectal cancer. The limited treatment outcomes for these diseases underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple mouse models, with no observable toxicity.Methods Cell proliferation and cell cycle progression were analyzed after loss of LSF activity, using HeLa cells as a model cancer cell line responsive to FQI1. In addition, results were compared after treatment with either FQI1 or siRNA targeting LSF to test for biological specificity of targeting LSF by FQI1.Results Cellular phenotypes observed upon FQI1 treatment were due specifically to the loss of LSF activity, as siRNA targeting LSF produced highly similar phenotypes. Inhibition of LSF activity by either mechanism induced a strong delay prior to metaphase during progression through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence.Conclusions Specific inhibition of LSF by small molecules or siRNA results in mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings not only confirm that LSF is a promising target for cancer treatment, but also that FQIs are promising compounds for obtaining therapeutic effects for multiple LSF-driven cancers with unmet medical need.