Regulation of the unfolded protein response through ATF4 and FAM129A in prostate cancer

Abstract

Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One such critical pathway in eukaryotic cells is the unfolded protein response (UPR) that is important in normal physiology as well as disease states, including cancer. Since UPR can serve as a lever between survival and death, regulated control of its activity is critical for tumor formation and growth although the underlying mechanisms are poorly understood. Here we show that one of the main transcriptional effectors of UPR, activating transcription factor 4 (ATF4), is essential for prostate cancer (PCa) growth and survival. Using systemic unbiased gene expression and proteomic analyses, we identified a novel direct ATF4 target gene, family with sequence similarity 129 member A (FAM129A), which is critical in mediating ATF4 effects on prostate tumorigenesis. Interestingly, FAM129A regulated both PERK and eIF2α in a feedback loop that differentially channeled the UPR output. ATF4 and FAM129A protein expression is increased in patient PCa samples compared with benign prostate. Importantly, in vivo therapeutic silencing of ATF4-FAM129A axis profoundly inhibited tumor growth in a preclinical PCa model. These data support that one of the canonical UPR branches, through ATF4 and its target gene FAM129A, is required for PCa growth and thus may serve as a novel therapeutic target.

Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program

“…In this methionine--dependent context, cells co-opt Gcn4, which is conventionally viewed as a 'survival/stress' transcription factor, to provide this supply of metabolic precursors. Relevantly, recent studies of the mammalian ortholog of Gcn4 (ATF4) now report high ATF4 activity in several cancers (Pällmann et al, 2019;Singleton and Harris, 2012;Tameire et al, 2019;Ye et al, 2010). These studies suggest that ATF4 induction is critical for tumor progression during nutrient limitation, possibly by providing otherwise limiting metabolites (Tameire et al, 2019;Ye et al, 2010).…”

DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4

“…Since ATF4 helps cells cope with stress, it plays a central role in the survival of cancer cells, which are exposed to proteotoxic stress, hypoxia, nutrient stress, DNA damage, and oxidative stress. For instance, ATF4 is required for transformation of fibroblasts by H-rasV 12 , it is essential for prostate cancer cells to grow and survive 23 , and it has been implicated in chemotherapy resistance 50 . We therefore studied the functional consequences of DENR-dependent ATF4 translation.…”

“…ATF4 is also a developmental transcription factor required for proper formation of the hematopoietic system, brain, bone, and eye [17][18][19][20][21] . Finally, the ISR and ATF4 are mediators of tumor resistance to stress and therapy [22][23][24][25][26][27][28] . Human ATF4 has three uORFs in its 5′ UTR.…”

Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program

“…Although it is primarily studied in the context of starvation, during a methionine driven growth program Gcn4 activity fuels the synthesis of required biosynthetic precursors to drive growth. Interestingly, such scenarios are also observed in several tumors, where the mammalian ortholog of Gcn4 (ATF4) is induced and helps in tumor proliferation (57)(58)(59)(60). The mechanisms of induction of ATF4 in these contexts have not been well studied, and the mechanism observed in this study is plausible in those contexts of high growth.…”