Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells

Abstract

Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and redifferentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that inhibition of the epigenetic modification enzyme enhancer of zeste homolog 2 (EZH2), histone deacetylases 1 and 3 (HDAC1 and -3), lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines. The regulatory effect of these enzymes in neuronal differentiation resided in their intrinsic activity in embryonic neural precursor/progenitor cells. We further found that a major part of pan-cancer-promoting genes and the signal transducers of the pan-cancer-promoting signaling pathways, including the epithelial-to-mesenchymal transition (EMT) mesenchymal marker genes, display neural specific expression during embryonic neurulation. In contrast, many tumor suppressor genes, including the EMT epithelial marker gene that encodes cadherin 1 (), exhibited non-neural or no expression. This correlation indicated that cancer cells and embryonic neural cells share a regulatory network, mediating both tumorigenesis and neural development. This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells.

Neural stemness contributes to cell tumorigenicity

“…Cell migration/invasion assays Experiments were performed as described [10]. C2C12 WT and C2C12 Myod1-/cells were subjected to migration/invasion assays without further treatment.…”

“…Neural stemness genes, which are responsible for self-renewal and differentiation of NSCs/NPCs, play cancer-promoting roles or are upregulated during tumorigenesis [10,12]. Upregulation of these genes suggests a continuing promotion of tumor growth.…”

“…In contrast, a substantial part of cancer repressor genes or the genes downregulated/silenced in cancer cells is expressed in non-neural cells or is not expressed in embryos [10]. Major genes/factors that regulate cancer cell malignant features are also expressed speci cally in embryonic neural cells and/or play critical roles in neural development [10][11][12]. The similarity in regulatory network is not found between cancer cells and other types of cells, e.g., the mesenchymal cells.…”

“…We showed previously that cells of different cancer types were characteristic of neural stem/progenitor cells (NSCs/NPCs) because 1) cancer cells exhibit neuronal differentiation potential when endogenous cancer-promoting factors are inhibited, and 2) expression of most (if not all) cancer promoting genes or genes being upregulated/activated in cancer cells is neural speci c or at least enriched in embryonic neural cells [10,11]. In contrast, a substantial part of cancer repressor genes or the genes downregulated/silenced in cancer cells is expressed in non-neural cells or is not expressed in embryos [10]. Major genes/factors that regulate cancer cell malignant features are also expressed speci cally in embryonic neural cells and/or play critical roles in neural development [10][11][12].…”

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

“…Ketorolac salt was found to interact with DDX3X and revealed the growth inhibitory effect in oral cancer cell model [61]. In liver hepatocellular HepG2 cells, treatment with 5-aza-2 -deoxycytidine (decitabine), SP2509, EPZ-6438 (tazemetostat), and TSA (trichostatin A) resulted in the reduced expression of DDX3X at the RNA level [62]. Furthermore, 1,3,4-thiadiazole is a novel DDX3X ATPase activity inhibitor synthesized for countering HIV-1 effects [63].…”