title: 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.
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: Xiao-Yong
authors: XY
authors: Zhang
authors: Harla K
authors: HK
authors: Pfeiffer
authors: Hestia S
authors: HS
authors: Mellert
authors: Timothy J
authors: TJ
authors: Stanek
authors: Robyn T
authors: RT
authors: Sussman
authors: Alpana
authors: A
authors: Kumari
authors: Duonan
authors: D
authors: Yu
authors: Isidore
authors: I
authors: Rigoutsos
authors: Andrei
authors: A
authors: Thomas-Tikhonenko
authors: Hans E
authors: HE
authors: Seidel
authors: Lewis A
authors: LA
authors: Chodosh
authors: Graham
authors: G
authors: Packham
authors: Renato
authors: R
authors: Baserga
authors: Steven B
authors: SB
authors: McMahon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D056426:Genetic Loci; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors