Journal Article

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

Willoughby, Jennifer L. S., Pedamallu, Chandra Sekhar, Shah, Jagesh, Stoiber, Patrick, Hansen, Ulla, George, Kelly, Shin, Hyunjin, Chin, Hang Gyeong, Roberto, Mark P., Schaus, Scott E., Fitzgerald, Kevin

2020

Overview

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 and disappointing clinical results, in particular, for hepatocellular carcinoma in molecularly targeted therapies targeting cellular receptors and kinases, underscore the need for molecularly targeting novel mechanisms. LSF small molecule inhibitors, Factor Quinolinone Inhibitors (FQIs), have exhibited robust anti-tumor activity in multiple pre-clinical models, with no observable toxicity. Methods To understand how the LSF inhibitors impact cancer cell proliferation, we characterized the cellular phenotypes that result from loss of LSF activity. Cell proliferation and cell cycle progression were analyzed, using HeLa cells as a model cancer cell line responsive to FQI1. Cell cycle progression was studied either by time lapse microscopy or by bulk synchronization of cell populations to ensure accuracy in interpretation of the outcomes. In order to test for biological specificity of targeting LSF by FQI1, results were compared after treatment with either FQI1 or siRNA targeting LSF. Results Highly similar cellular phenotypes are observed upon treatments with FQI1 and siRNA targeting LSF. Along with similar effects on two cellular biomarkers, inhibition of LSF activity by either mechanism induced a strong delay or arrest prior to metaphase as cells progressed through mitosis, with condensed, but unaligned, chromosomes. This mitotic disruption in both cases resulted in improper cellular division leading to multiple outcomes: multi-nucleation, apoptosis, and cellular senescence. Conclusions These data strongly support that cellular phenotypes observed upon FQI1 treatment are due specifically to the loss of LSF activity. Specific inhibition of LSF by either small molecules or siRNA results in severe mitotic defects, leading to cell death or senescence - consequences that are desirable in combating cancer. Taken together, these findings confirm that LSF is a promising target for cancer treatment. Furthermore, this study provides further support for developing FQIs or other LSF inhibitory strategies as treatment for LSF-related cancers with high unmet medical needs.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Antitumor agents / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Benzodioxoles - pharmacology / Benzodioxoles - therapeutic use / Biochemistry / Biomedical and Life Sciences / Biomedicine / Biotechnology industries / Cancer Research / Cell and molecular biology / Cell cycle / Cell Cycle Checkpoints - drug effects / Cell Cycle Checkpoints - genetics / Cell death / Cell division / Cell Division - drug effects / Cell Division - genetics / Cell proliferation / Cellular Senescence - drug effects / Cellular Senescence - genetics / Chromosomes / Chromosomes, Human - drug effects / Chromosomes, Human - genetics / Chromosomes, Human - metabolism / Colorectal cancer / Colorectal carcinoma / Deoxyribonucleic acid / DNA / DNA-Binding Proteins - antagonists & inhibitors / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug Screening Assays, Antitumor / Drug therapy / Experiments / Flow cytometry / FQI1 / Genetic aspects / Genetic research / Health aspects / Health Promotion and Disease Prevention / HeLa Cells / Hepatocellular carcinoma / Humans / Intravital Microscopy / Kinases / Lenvatinib / Liver cancer / LSF / Medical prognosis / Medicine/Public Health / Metaphase / Microscopy / Mitosis / Molecular Targeted Therapy - methods / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Oncogenes / Oncology / Phenols / Phenotypes / Prognosis / Quinolones - pharmacology / Quinolones - therapeutic use / Regorafenib / Research Article / RNA, Small Interfering - metabolism / Senescence / siRNA / Small molecule inhibitors / Sorafenib / Surgical Oncology / Synchronization / Therapeutic applications / Time-Lapse Imaging / Toxicity / Transcription factors / Transcription Factors - antagonists & inhibitors / Transcription Factors - genetics / Transcription Factors - metabolism / Tumors