HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma

Abstract

Medulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood.Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as a therapeutic tool to target this cell population. Here, we observed changes in the stemness phenotype induced by HDAC inhibition in MB. Analyses of MB tumor samples showed that the stemness markers BMI1 and CD133 are expressed in all molecular subgroups of MB. We then treated human MB cells with the HDAC inhibitor (HDACi) sodium butyrate (NaB). Increased acetylation mediated by NaB reduced cell viability and expression of BMI1 and CD133. Activation of extracellular-regulated kinase (ERK) signaling was also decreased after treatment with NaB.Enrichment analysis of genes associated with CD133 or BMI1 expression showed mitogenactivated protein kinase (MAPK)/ERK signaling and related pathways as the most enriched processes. We went on to use the mitogen-activated protein kinase kinase (MEK) inhibitor U0126 to explore the role of MAPK/ERK pathway. MEK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be more effective in reducing MB proliferation than single-drug treatments, through modulation of the stemness phenotype of MB cells. 5 Keywords: Histone deacetylase Extracellular-regulated kinase Stemness Medulloblastoma Brain tumor 6

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

“…MAPK signaling is induced by extracellular cues and transmitted through a tier of sequentially activated receptors, adaptor proteins, small GTPases and kinases that control differentiation, proliferation, viability and migration of cells and tissues. Aberrant activation of MAPK signaling, for example by the amplification of a pathway-inducing receptor, by the mutational alterations of receptors or signal-transmitting intermediates or by the inactivation of pathway repressors is observed in multiple tumors including medulloblastoma (MB) [1] , [2] , [3] , [4] , [5] , [6] , the most common malignant brain tumor in children. Molecular profiling of MB defined four subgroups with a total of 12 subtypes [7] , [8] , with variable demographic, clinical and molecular features [9] .…”

Overview and recent advances in the targeting of medulloblastoma cancer stem cells

“…and subsequently found to be a marker of normal human NSCs [77]. CD133 is also described as a CSC marker for many other solid tumors [55], and subsets of CD133+ cells have been found in all molecular subgroups of medulloblastoma [78].…”

“…Histone deacetylases (HDACs) modulate gene expression, and class I HDACs were shown to modulate Hedgehog signaling through Gli1 and Gli2 deacetylation, with resultant transcriptional activation [133]. HDAC inhibition has been shown to reduce medulloblastoma cell viability and also appears to promote differentiation as evidenced by decreased CD133 and BMI1 expression, and this effect was amplified with concurrent MEK1/2 inhibition [78,134]. Antitumor effects were also seen with both pharmacologic HDAC inhibition [135,136], and genetic knockdown of HDAC gene expression [136].…”

The Golgi Apparatus May Be a Potential Therapeutic Target for Apoptosis-Related Neurological Diseases

“…The CTF in the nucleus serves as a scaffold to tether ERK and p53, thereby promoting p53 phosphorylation and activation by ERK ( How and Shields, 2011 ). ERK is a mitogen-activated protein kinase, and its signaling cascade plays an important role in apoptosis ( Li et al, 2014 ; da Cunha Jaeger et al, 2020 ). p53 is an important tumor suppressor gene, and it is often involved in the transcriptional regulation of key pro-apoptotic genes, such as p53 upregulated modulator of apoptosis ( PUMA ) and hdm2 ( Khan et al, 2020 ).…”