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Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition., Introduction Prostate tumors are the most frequently diagnosed cancer in US men and a major health problem throughout the world. Apart from surgery and radiotherapy, androgen ablation is a standard [...]

Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition. [ABSTRACT FROM AUTHOR]

The overall goal of the annual Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop is to provide transdisciplinary training for scientists in energetics and cancer and clinical care. The 2022 Workshop included 27 early-to-mid career investigators (trainees) pursuing diverse TREC research areas in basic, clinical, and population sciences. The 2022 trainees participated in a gallery walk, an interactive qualitative program evaluation method, to summarize key takeaways related to program objectives. Writing groups were formed and collaborated on this summary of the 5 key takeaways from the TREC Workshop. The 2022 TREC Workshop provided a targeted and unique networking opportunity that facilitated meaningful collaborative work addressing research and clinical needs in energetics and cancer. This report summarizes the 2022 TREC Workshop's key takeaways and future directions for innovative transdisciplinary energetics and cancer research., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The transcription factor ETS variant 1 (ETV1) is capable of promoting prostate tumorigenesis. We demonstrate that ETV1 can be posttranslationally modified by covalent attachment of small ubiquitin-like modifier 1 (SUMO1) onto four different lysine residues. In human embryonic kidney 293T cells, mutation of these sumoylation sites stimulated the transactivation potential of ETV1 at the matrix metalloproteinase 1 (MMP1), but not Yes-associated protein 1 gene promoter, while ETV1 protein stability and intracellular localization remained unchanged. In stark contrast, sumoylation-deficient ETV1 was repressed in its ability to stimulate the MMP1 promoter and to cooperate with a histone demethylase, JmjC domain-containing 2A (JMJD2A), in LNCaP prostate cancer cells. Mutation of sumoylation sites enhanced the ability of ETV1 to interact with the histone deacetylase (HDAC) 1, but had basically no impact on complex formation with HDAC3 or JMJD2A. Further, compared to non-sumoylated ETV1, its sumoylated forms were less able to bind to the transcription factor, SMAD family member 4. Lastly, in contrast to wild-type ETV1, sumoylation-deficient ETV1 repressed LNCaP cell growth. Altogether, these data suggest that sumoylation modulates ETV1 function in a cell type-specific manner, possibly by altering the spectrum of transcriptional cofactors being recruited. Notably, SUMO pathway components SUMO1, ubiquitin-like modifier activating enzyme 2 and ubiquitin conjugating enzyme 9 were upregulated in prostate tumors, implying that enhanced sumoylation indeed promotes ETV1's oncogenic activity during prostate cancer formation., Competing Interests: None., (IJCEP Copyright © 2021.)

PSMD10, also known as gankyrin, is associated with the proteasome and has been shown to be an oncoprotein in the liver. Here, we report that PSMD10 expression is stimulated by the histone demethylase JMJD2A/KDM4A and its interaction partner, the ETV1 transcription factor, in LNCaP prostate cancer cells. Global analysis of expression patterns revealed that PSMD10 mRNA levels are positively correlated with those of both JMJD2A and ETV1. In human prostate tumors, PSMD10 is highly overexpressed at the protein level and correlates with JMJD2A overexpression; further, PSMD10 expression is enhanced in the prostates of transgenic JMJD2A mice. Moreover, PSMD10 is particularly overexpressed in high Gleason score prostate tumors. Downregulation of PSMD10 in LNCaP prostate cancer cells impaired their growth, indicating that PSMD10 may exert a pro-oncogenic function in the prostate. Lastly, we observed that PSMD10 expression is correlated to YAP1, a component of the Hippo signaling pathway and whose gene promoter is regulated by JMJD2A, and that PSMD10 can cooperate with YAP1 in stimulating LNCaP cell growth. Altogether, these data indicate that PSMD10 is a novel downstream effector of JMJD2A and suggest that inhibition of the JMJD2A histone demethylase by small molecule drugs may be effective to curtail the oncogenic activity of PSMD10 in various PSMD10-overexpressing tumors., Competing Interests: Disclosure of conflict of interest Ralf Janknecht is a scientific advisor for Chrysalis Therapeutics. The other authors have declared that no conflict of interest exists.

Prostate cancer is characterized by the recurrent translocation of ETS transcription factors, including ETS variant 1 (ETV1) [also known as ETS-related 81 (ER81)]. Transgenic ETV1 mice develop prostatic intraepithelial neoplasia, yet the mechanisms by which ETV1 exerts its deleterious function remain largely unexplored. In this study, we demonstrated that ETV1 is capable of binding to the matrix metalloproteinase-7 (MMP-7) gene promoter both in vitro and in vivo. ETV1 stimulated the activity of the MMP-7 promoter, which was suppressed upon mutation of two ETV1 binding sites located within 200 base pairs upstream of the MMP-7 transcription start site. ETV1 overexpression in human LNCaP prostate cancer cells induced endogenous MMP-7 gene transcription, whereas ETV1 downregulation had the opposite effect. While MMP-7 overexpression did not influence LNCaP cell proliferation, it increased cell migration, which may be important during later stages of tumorigenesis. Finally, MMP-7 mRNA was significantly overexpressed in human prostate tumors compared to normal tissue. Together, these results showed that MMP-7 is a bona fide ETV1 target gene, implicating that MMP-7 upregulation is partially responsible for the oncogenic effects of ETV1 in the prostate.