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

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.

Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases

“…The fusion partners for HNRMS with TFCP2 translocation are FUS (in our cohort, 7/11, 64%; in all reported cases, 18/27, 67%) and EWSR1 (in our cohort, 4/11, 36%; in all reported cases, 9/27, 33%) 5–14 . TFCP2 encodes the LSF oncoprotein, which is a transcription factor that functions as a coactivator for YAP, a key transcription factor downstream of the Hippo and Wnt signalling pathway 22,23 . LSF overexpression has been observed in multiple cancers, e.g.…”

“…LSF overexpression has been observed in multiple cancers, e.g. hepatocellular, breast, pancreatic, and colorectal carcinomas, and is associated with a poor prognosis 22,24 . Factor quinolinone inhibitors (FQIs), which constitute a family of small‐molecule inhibitors of LSF, was recently identified to inhibit tumour growth of hepatocellular carcinoma in vitro and in animal models 22 .…”

“…hepatocellular, breast, pancreatic, and colorectal carcinomas, and is associated with a poor prognosis 22,24 . Factor quinolinone inhibitors (FQIs), which constitute a family of small‐molecule inhibitors of LSF, was recently identified to inhibit tumour growth of hepatocellular carcinoma in vitro and in animal models 22 . It remains to be determined whether patients with RMSs with TFCP2 ‐based translocations will benefit from targeted FQI strategies.…”