Inhibition of the Single Downstream Target BAG1 Activates the Latent Apoptotic Potential of MYC

Abstract

Aberrant MYC expression is a common oncogenic event in human cancer. Paradoxically, MYC can either drive cell cycle progression or induce apoptosis. The latent ability of MYC to induce apoptosis has been termed "intrinsic tumor suppressor activity," and reactivating this apoptotic function in tumors is widely considered a valuable therapeutic goal. As a transcription factor, MYC controls the expression of many downstream targets, and for the majority of these, it remains unclear whether or not they play direct roles in MYC function. To identify the subset of genes specifically required for biological activity, we conducted a screen for functionally important MYC targets and identified BAG1, which encodes a prosurvival chaperone protein. Expression of BAG1 is regulated by MYC in both a mouse model of breast cancer and transformed human cells. Remarkably, BAG1 induction is essential for protecting cells from MYC-induced apoptosis. Ultimately, the synthetic lethality we have identified between MYC overexpression and BAG1 inhibition establishes a new pathway that might be exploited to reactivate the latent apoptotic potential of MYC as a cancer therapy.

microRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas

“…Interestingly, both MAD2L1 and BAG1 have been shown to be induced by MYC (27,28), and we confirmed that both genes were up-regulated in MCF10A-MYC cells. Consistent with the results obtained in B cells, induction of miR-28 led to a reduction of MAD2L1 and BAG1 (Fig.…”

“…Deregulation of ERK signaling is found in many different cancers, including B-NHL, and its inhibition is also associated with an increase in apoptosis (31,32), including MYC-induced apoptosis (28). Thus, elevated BAG1 levels can protect the cells from apoptosis and, by activating ERK1/2, may favor survival and proliferation in lymphomas lacking miR-28 expression.…”

“…Interestingly, some of the miR-28 direct targets genes, such as MAD2L1 and BAG1, have been shown to be transactivated by MYC (27,28), whereas ERK1/2 signaling is involved in the stabilization of MYC protein (38). These observations, together with their mutually exclusive expression in GC B cells, suggest the presence of multiple feedback loops between MYC and miR-28.…”

MYC and the Control of Apoptosis

“…In animal tumor models, loss of even a single copy of the BAG-1 gene decreases tumor formation (Gotz et al 2004), presumably owing to heightened apoptosis of the nascent tumor cells. Our analysis showed that induction of BAG-1 by MYC is a critical event in dampening the latent apoptotic effects that MYC overexpression otherwise exerts (Zhang et al 2011). Although BAG-1 is expressed as multiple protein isoforms with potentially distinct functions and has many client proteins beyond BCL-2 (Wang et al 1996;Luders et al 2000;Cato and Mink 2001;Lin et al 2001;Arhel et al 2003), these studies provide further evidence that modulating the prosurvival/proapoptotic balance in the BCL pathway is an important means by which MYC controls its biological effects.…”

“…An additional link between regulation of the BCL-2 pathway and MYC's apoptotic effects was shown in recent studies from our group that identified the BAG-1 gene product as a critical, direct downstream target of MYC (Zhang et al 2011). BAG-1 was first isolated as a BCL-2 chaperone that has potent prosurvival effects (Takayama et al 1995).…”