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The six transmembrane protein of prostate 2 ( STAMP2) is an androgen‐regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage‐independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target. Synopsis The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression. During prostate cancer progression, STAMP2 expression is deregulated and correlated with tumor grade and response to treatment. STAMP2 knockdown inhibits cell proliferation, colony formation, and anchorage‐independent growth, while significantly increasing apoptosis. STAMP2 significantly increases ROS through its iron reductase activity and depletes NADPH levels resulting in ATF4 expression. Therapeutic STAMP2 silencing by systemically administered nanoliposomal siRNA profoundly inhibits tumor growth in preclinical prostate cancer models suggesting that STAMP2 may serve as a novel therapeutic target. Graphical Abstract The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression.

Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity.

The central importance of translational control by posttranslational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and subsequently cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, by mass spectrometry we observed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool to manipulate hypusine modification in a temporal and spatial manner, both to analyze how this unique modification normally functions in vivo, as well as how it contributes to different pathological conditions.

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.

The six transmembrane protein of prostate 2 ( STAMP 2) is an androgen‐regulated gene whose mRNA expression is increased in prostate cancer ( PC a). Here, we show that STAMP 2 protein expression is increased in human PC a compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP 2 significantly increased reactive oxygen species ( ROS ) in PC a cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP 2 expression in PC a cells inhibited proliferation, colony formation, and anchorage‐independent growth, and significantly increased apoptosis. Furthermore, STAMP 2 effects were, at least in part, mediated by activating transcription factor 4 ( ATF 4), whose expression is regulated by ROS . Consistent with in vitro findings, silencing STAMP 2 significantly inhibited PC a xenograft growth in mice. Finally, therapeutic silencing of STAMP 2 by systemically administered nanoliposomal si RNA profoundly inhibited tumor growth in two established preclinical PC a models in mice. These data suggest that STAMP 2 is required for PC a progression and thus may serve as a novel therapeutic target. image The androgen‐regulated transmembrane protein STAMP 2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP 2 regulates cell proliferation by increasing ROS , which in turn activate ATF 4 expression. During prostate cancer progression, STAMP 2 expression is deregulated and correlated with tumor grade and response to treatment. STAMP 2 knockdown inhibits cell proliferation, colony formation, and anchorage‐independent growth, while significantly increasing apoptosis. STAMP 2 significantly increases ROS through its iron reductase activity and depletes NADPH levels resulting in ATF 4 expression. Therapeutic STAMP 2 silencing by systemically administered nanoliposomal si RNA profoundly inhibits tumor growth in preclinical prostate cancer models suggesting that STAMP 2 may serve as a novel therapeutic target.