Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model

Rajasekaran, Devaraja; Siddiq, Ayesha; Willoughby, Jennifer L. S.; Biagi, Jessica M.; Christadore, Lisa M.; Yunes, Sarah A.; Gredler, Rachel; Jariwala, Nidhi; Robertson, Chadia L.; Akiel, Maaged; Shen, Xue‐Ning; Subler, Mark A.; Windle, Jolene J.; Schaus, Scott E.; Fisher, Paul B.; Hansen, Ulla; Sarkar, Devanand

doi:10.18632/oncotarget.4656

Cited by 25 publications

(51 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Rajasekaran et al . ). However, the expression level of TFCP2 is decreased in melanoma, and up‐regulated TFCP2 suppresses melanoma cell growth and increases the percentage of G1 phase cells (Goto et al .…”

Section: Discussionmentioning

confidence: 97%

“…Overexpressed TFCP2 functions as an oncogenic role in HCC pathogenesis. Inhibition of TFCP2 abrogates HCC cell growth and metastasis in vivo and in vitro (Santhekadur et al 2012;Rajasekaran et al 2015). However, the expression level of TFCP2 is decreased in melanoma, and up-regulated TFCP2 suppresses melanoma cell growth and increases the percentage of G1 phase cells (Goto et al 2016).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The aberrantly expressed long non‐coding RNA in the substantia nigra and corpus striatum of Nrf2‐knockout mice

Liu

Kang

et al. 2017

Journal of Neurochemistry

View full text Add to dashboard Cite

Nuclear factor erythroid 2 like 2 (Nrf2) functions as a neuroprotective agent in Parkinson's disease (PD). This study aimed to investigate the key long non-coding RNAs (lncRNAs) correlated with Nrf2, which might provide valuable information for the exploration of pathogenesis of PD. The lncRNA and mRNA expression profiling of substantia nigra and corpus striatum of Nrf2 (-/-) mice model was obtained from microarray analysis. The animal experiments conducted for this study were approved by the ethics committee of Hebei Medical University. Bioinformatics analyses were conducted, including differentially expressed lncRNAs/mRNA (differentially expressed lncRNA, DEL/differentially expressed mRNA, DEM) identification, DEL-DEM coexpression network construction, and biological functions prediction. Quantitative real-time polymerase chain reaction (qRT-PCR) was subjected to validate abnormally expressed DELs and DEMs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice model. A total of 48 DELs (37 down-regulated and 11 up-regulated) were identified both in Nrf2 (-/-) substantia nigra and corpus striatum; 96 DEMs and 643 DEMs were identified in the substantia nigra and corpus striatum, respectively. DEL-DEM coexpressed network was constructed. LncRNA AK076880, AK036620, and AK020330 had high connectivity with DEMs both in the substantia nigra and corpus striatum. These DEMs were significantly enriched in signaling pathways such as the calcium signaling pathway, Huntington's disease, Alzheimer's disease, mitogen-activated protein kinase (MAPK) signaling pathway, and the Wnt signaling pathway. Generally, qRT-PCR validation results of selected DEMs and DELs were consistent with microarray data. The dysregulated DELs and DEMs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice were identified. Our results might provide useful information for further exploring the pathogenesis mechanism of PD.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

The aberrantly expressed long non‐coding RNA in the substantia nigra and corpus striatum of Nrf2‐knockout mice

Liu

Kang

et al. 2017

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, fluorescent staining of synchronized cells for DNA and tubulin demonstrated that when control cells completed mitosis and re-entered G1, FQI-treated cells generally remained in mitosis with condensed but unaligned DNA (17). In order to elucidate the basis for these FQI1mediated mitotic defects and their consequences in greater detail, and over a range of FQI1 concentrations, we synchronized HeLa cells, which demonstrate the same phenotype, with a double thymidine block (Fig.…”

Section: Chemical Inhibition Of Lsf Induces Mitotic Defectsmentioning

confidence: 99%

“…Phenotypically, FQIs inhibit growth of hepatocellular carcinoma cells in vitro. They also inhibit hepatocellular carcinoma tumor growth in vivo in multiple mouse models, including a mouse endogenous liver tumor model (17). In all cases, inhibition of tumor growth occurred in the absence of toxicity, as assessed by liver injury markers, histopathology of tissues with rapid cell turnover, or blood cell counts (18).…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanisms by which LSF promotes cancer cell survival has not been well characterized, although initial data indicated that FQIs induce a "prometaphase-like" arrest in hepatocellular carcinoma cells (17). Clarifying the pathways by which inhibition of LSF leads to cell death is important to further support the candidacy of FQIs as a molecular therapy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

George

Roberto³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

A Cell‐Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer‐Specific Synthetic Lethality

Son,

Kim,

Choi

et al. 2023

Advanced Science

View full text Add to dashboard Cite

Despite advances in precision oncology, cancer remains a global public health issue. In this report, proof‐of‐principle evidence is presented that a cell‐penetrable peptide (ACP52C) dissociates transcription factor CP2c complexes and induces apoptosis in most CP2c oncogene‐addicted cancer cells through transcription activity‐independent mechanisms. CP2cs dissociated from complexes directly interact with and degrade YY1, leading to apoptosis via the MDM2‐p53 pathway. The liberated CP2cs also inhibit TDP2, causing intrinsic genome‐wide DNA strand breaks and subsequent catastrophic DNA damage responses. These two mechanisms are independent of cancer driver mutations but are hindered by high MDM2 p60 expression. However, resistance to ACP52C mediated by MDM2 p60 can be sensitized by CASP2 inhibition. Additionally, derivatives of ACP52C conjugated with fatty acid alone or with a CASP2 inhibiting peptide show improved pharmacokinetics and reduced cancer burden, even in ACP52C‐resistant cancers. This study enhances the understanding of ACP52C‐induced cancer‐specific apoptosis induction and supports the use of ACP52C in anticancer drug development.

show abstract

Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model

Abstract: ABSTRACT

Cited by 25 publications

References 29 publications

The aberrantly expressed long non‐coding RNA in the substantia nigra and corpus striatum of Nrf2‐knockout mice

The aberrantly expressed long non‐coding RNA in the substantia nigra and corpus striatum of Nrf2‐knockout mice

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

A Cell‐Penetrant Peptide Disrupting the Transcription Factor CP2c Complexes Induces Cancer‐Specific Synthetic Lethality

Contact Info

Product

Resources

About