Abstract
Reactivation of apoptotic pathways is an attractive strategy for patients with treatment-resistant B-cell lymphoma. The tumor suppressor, p53 is central for apoptotic response to multiple DNA damaging agents used to treat aggressive B-cell lymphomas, including etoposide. It has been demonstrated that etoposide induced DNA damage and therapeutic efficacy is enhanced by combination with inhibitors of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). Further, EZH2 was identified to regulate cell fate decisions in response to DNA damage. Using B-cell lymphoma cell lines resistant to etoposide induced cell death; we show that p53 is dramatically down regulated and MDMX, a negative regulator of p53, is significantly up regulated. However, these cell lines remain responsive to etoposide mediated DNA damage and exhibit cell cycle inhibition and induction of senescence. Furthermore, chemical inhibition of EZH2 directs DNA damage to a predominant p53 dependent apoptotic response associated with loss of MDMX and BCL-XL. These data provide confirmation of EZH2 in determining cell fate following DNA damage and propose a novel therapeutic strategy for patients with aggressive treatment-resistant B-cell lymphoma.
Highlights
The tumor suppressor TP53 (p53) is inactivated or mutated in multiple cancers, including B-cell lymphoma [1]
We demonstrate that etoposide treatment of multidrug resistant B-cell lymphomas results in p53 activation and DNA damage associated with induction of cell cycle arrest and senescence
Because of the observed resistance to etoposide mediated cell death, we investigated if etoposide still induced DNA damage
Summary
The tumor suppressor TP53 (p53) is inactivated or mutated in multiple cancers, including B-cell lymphoma [1]. P53 action in response to DNA damage most often occurs by the activation of genes involved in cell-cycle arrest, senescence, and apoptosis [2]. Genotoxic chemotherapy agents such as etoposide mediate therapeutic efficacy via p53-DNA damage signaling. Etoposide represents one of multiple genotoxic chemotherapy options used in conjunction with rituximab to treat aggressive B-cell lymphomas. Multiple studies indicate that p53-mediated senescence impairs the apoptotic response to chemotherapy in various cancers [3,4,5,6], resulting in chemo-resistance and limited patient response to such therapies. EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) resulting in gene suppression and its action is implicated in cell proliferation, apoptosis and senescence [8]
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