HDAC Inhibition Induces Cell Cycle Arrest and Mesenchymal-Epithelial Transition in a Novel Pleural-Effusion Derived Uterine Carcinosarcoma Cell Line

Abstract

Objective: Uterine carcinosarcoma (UCS) is a rare but highly aggressive malignancy with biphasic growth pattern. This morphology can be attributed to epithelial-mesenchymal transition (EMT) that often associates with tumor invasion and metastasis. Accordingly, we analyzed a novel patient-derived preclinical model to explore whether EMT is a potential target in UCS.Methods: A novel UCS cell line (PF338) was established from the malignant pleural effusion of a 59-year-old patient at time of disease progression. Immunohistochemistry was performed in primary and metastatic tumor lesions. Oncogenic mutations were identified by next-generation sequencing. Viability assays and cell cycle analyses were used to test in vitro sensitivity to different standard and novel treatments. E-cadherin, β-catenin and pSMAD2 expressions were measured by immunoblot.Results: Whereas immunohistochemistry of the metastatic tumor showed a predominantly sarcomatous vimentin positive tumor that has lost E-cadherin expression, PF338 cells demonstrated biphasic growth and carried mutations in KRAS, PIK3CA, PTEN and ARID1A. PF338 tumor cells were resistant to MEK- and TGF-β signaling-inhibition but sensitive to PIK3CA- and PARP-inhibition and first-line chemotherapeutics. Strikingly, histone deacetylase (HDAC) inhibition markedly reduced cell viability by inducing a dose-dependent G0/1 arrest and led to mesenchymal-epithelial transition as evidenced by morphological change and increased E-cadherin and β-catenin expression.Conclusions: Our data suggest that HDAC inhibition is effective in a novel UCS cell line by interfering with both viability and differentiation. These findings emphasize the dynamic manner of EMT/MET and epigenetics and the importance of molecular profiling to pave the way for novel therapies in UCS.

Vorinostat (SAHA) and Breast Cancer: An Overview

“…Histone deacetylase inhibitors (HDIs) selectively modulate gene transcription through the changes in the structure of proteins involved in transcriptional machinery [ 56 , 57 , 58 ]. Besides altering gene transcription, HDACs affect non-histone targets, including transcriptional factors [ 31 , 32 , 59 , 60 , 61 ], hormonal receptors [ 62 , 63 , 64 ] as well as signaling mediators [ 65 , 66 ]. These targets could also be modulated by HDIs.…”

Expanding the coverage of regulons from high-confidence prior knowledge for accurate estimation of transcription factor activities

“…The aforementioned histone deacetylase, HDAC5, was predicted to have an increased activity with the CollecTRI regulons. HDCA5 inhibition with pan-HDAC inhibitors has been reported to lead to cell cycle arrest in UCEC ( 72 ), suggesting a positive role of the TF in cancer development, which is also reflected in the increased predicted activity. The HCFC1 transcription factor has an immunomodulatory role in cancer by inhibiting immune responses, and by promoting tumor growth and vascularization ( 73 ).…”

Endometrial carcinosarcoma

“…The epithelial–mesenchymal transition is the process by which epithelial cells lose their polarity and intercellular junctions and become multipotent mesenchymal cells with invasion and metastatic properties and the ability to differentiate in several cell types. The epithelial–mesenchymal transition is crucial in nearly all cancers and, notably, plays a key role in the pathogenesis of sarcomatous trans-differentiation from carcinomatous elements in endometrial carcinosarcoma 118 119. Endometrial carcinosarcomas with sarcoma dominance and heterologous sarcomatous component display a higher epithelial–mesenchymal transition and have been associated with poorer outcomes than homologous ones.…”

“…The epithelial–mesenchymal transition is regulated by complex networks involving transcriptional factors, growth factors, and cytokine signaling pathways, such as the transforming growth factor TGF-β1, Wnt, JAK/STAT, and MAPK cascade. In particular, TGF-β regulates a key pathway in the epithelial–mesenchymal transition process and may be a potential target 118 119. A phase IB trial (NCT03206177) is currently investigating the feasibility of combining galunisertib (TGF-β1 inhibitor) with the paclitaxel/carboplatin doublet in patients with newly diagnosed, persistent, or recurrent endometrial carcinosarcoma (Table 5).…”