Abstract
Epigenetic alterations, including dysregulated DNA methylation and histone modifications, govern the progression of colorectal cancer (CRC). Cancer cells exploit epigenetic regulation to control cellular pathways, including apoptotic and metastatic signals. Since aberrations in epigenome can be pharmacologically reversed by DNA methyltransferase and histone deacetylase inhibitors, epigenetics in combination with standard agents are currently envisaged as a new therapeutic frontier in cancer, expected to overcome drug resistance associated with current treatments. In this study, we challenged this idea and demonstrated that the combination of azacitidine and romidepsin with IFN-α owns a high therapeutic potential, targeting the most aggressive cellular components of CRC, such as metastatic cells and cancer stem cells (CSCs), via tight control of key survival and death pathways. Moreover, the antitumor efficacy of this novel pharmacological approach is associated with induction of signals of immunogenic cell death. Of note, a previously undisclosed key role of IFN-α in inducing both antiproliferative and pro-apoptotic effects on CSCs of CRC was also found. Overall, these findings open a new frontier on the suitability of IFN-α in association with epigenetics as a novel and promising therapeutic approach for CRC management.
Highlights
Colorectal cancer (CRC) develops upon a multistep process in which genetic mutations and epigenetic alterations drive tumor initiation, progression and metastatic growth [1,2,3]
Because it has been reported that Immunogenic cell death (ICD) is a crucial component of some antineoplastic treatments and that type I IFN (IFN-I) are implicated in this process [29, 41], we evaluated the capability of IFN-α to cooperate with epigenetic drugs in inducing this type of cellular demise
This study provides the first evidence that IFN-α cooperates with epigenetic drugs in inducing direct and immune-mediated antitumor effects on both metastatic cells and cancer stem cell (CSC) of colorectal cancer (CRC)
Summary
Colorectal cancer (CRC) develops upon a multistep process in which genetic mutations and epigenetic alterations drive tumor initiation, progression and metastatic growth [1,2,3]. KRAS mutations are key elements in determining CRC aggressiveness and resistance to therapy, since they activate cell proliferation, differentiation, survival, migration and apoptosis [4] Another key factor contributing to CRC aggressiveness is the elevated degree of cell heterogeneity due to both poorly differentiated metastatic cells, capable of migrating and invading basal lamina, and cancer stem cells (CSCs), a highly tumorigenic population with elevated self-renewing capability [5, 6]. Accumulating evidence indicates that abnormal changes in DNA methylation and histone modifications may act in concert in regulating expression of genes that drive the tumorigenic www.impactjournals.com/oncotarget process [12] Since both histone modifications and DNA methylation are potentially reversible by pharmacological treatments, they represent attractive targets for therapeutic strategies. A tight crosstalk between IFN-α and epigenetic signatures as well as the dysfunctional induction of IFN-α response in CSCs have been recently reported to associate with tumor progression [23,24,25]
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