Selected Articles from This Issue

Abstract

Screening and biomarker identification have improved prostate cancer outcomes, but prostate cancer progression remains a critical challenge. Mitochondria have garnered increasing attention in prostate and other cancers, and metabolic and non-metabolic mitochondrial contributions to cancer merit further investigation. In their study, Furnish and colleagues found that mitochondrial Rho GTPase 2 (MIRO2) expression is upregulated in recurrent and progressive prostate cancer, and that MIRO2 depletion via shRNA abrogates prostate cancer cell growth in vitro and in vivo. The authors identified MIRO2 protein interactors using MIRO2 immunoprecipitation and mass spectrometry and revealed general control nonderepressible (GCN1) is a MIRO2 binding partner. Mechanistically, the authors showed that MIRO2 facilitates GCN1-mediated activation of GCN2, which results in eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation and transcriptional upregulation of transcriptional activator 4 (ATF4). Immunohistochemistry data from prostate cancer xenografts implicated HIF1α as an oncogenic MIRO2 regulator. Overall, this work presents a previously unknown mechanism by which mitochondria promote prostate cancer progression and suggests that MIRO2 could be a useful therapeutic target for recurrent and progressive prostate cancer.Few therapeutic options exist for patients with metastatic prostate cancer. Furthermore, longitudinal study challenges and therapeutic effects on tumor biology render elucidating mechanisms that promote prostate cancer metastasis difficult. To address these issues and interrogate molecular drivers of prostate cancer metastasis, Van den Broeck and colleagues performed genomic analysis using samples from patients with localized or locally advanced prostate cancer who participated in longitudinal studies. The authors demonstrated that copy numbers of the gene encoding antizyme inhibitor 1 (AZIN1) are often amplified in samples that progressed to metastasis. Furthermore, abrogating AZIN1 expression using siRNA in prostate cancer cells decreased cell growth and migration in vitro and lung metastasis in vivo. By surveying transcriptomic changes induced by AZIN1 depletion, the authors noted that AZIN1 expression negatively correlates with expression of several collagens that can be processed into matrikines. Accordingly, culture media from AZIN1-deficient and collagen-overexpressing cells both decreased invasion and migration of prostate cancer cells in vitro. Altogether, this study presents a novel molecular facet of prostate cancer metastasis that could inform future therapeutic strategies.The MUC1 C-terminal subunit (MUC1-C) is known to promote cancer stem cell (CSC)-associated dedifferentiation, but whether MUC1-C contributes to dedifferentiation-associated transcription factor transactivation and chromatin remodeling is not clear. In their study, Bhattacharya and colleagues abrogate MUC1-C expression in prostate and breast cancer cells using shRNA and utilize Assay for Transposase-Accessible Chromatin using sequencing (ATAC-Seq) to demonstrate that MUC1-C influences chromatin remodeling in cancer cells. Integrative analysis using ATAC-Seq, RNA-Seq, and ChIP-Seq revealed that genes whose chromatin accessibility is modified by MUC1-C and that are differentially expressed upon MUC1-C depletion are enriched with FOS, JUN, and NEF2 transcription factor binding motifs. The authors went on to demonstrate that MUC1-C interacts with JUN, and that a MUC1-C/JUN/ARID1A complex increases chromatin accessibility and expression of critical CSC genes, including NOTCH1, EGR1, and LY6E, in both prostate and breast cancer cells. Overall, in addition to documenting a previously unrecognized interaction between MUC1-C and JUN, this study furthers the understanding of how MUC1-C contributes to transcription factor transactivation, chromatin remodeling, and CSC biology.Inhibiting DNA double-strand break (DSB) repair augments DNA damage-inducing therapeutic efficacy, but mechanisms underlying this therapeutic potentiation have not been fully elucidated. In their study, Carr and colleagues used DNA-PK inhibitor peposertib and DNA damage-inducing radiation to demonstrate that DNA DSB repair inhibition enhances both radiation-mediated cell death and inflammation. The authors found that peposertib augments radiation-induced chromosomal abnormalities, causing distorted chromosomal segregation and cell death in cancer cells in vitro. Immunofluorescent imaging revealed that cancer cells treated with radiation and peposertib harbor numerous micronuclei that associate with inflammatory cytosolic DNA sensor cGAS. Accordingly, treatment with radiation and peposertib induced expression of inflammatory signaling mediators and cytokines, as well as immunoregulatory programmed cell death ligand 1 (PD-L1). The authors used bintrafusp alfa in vivo to demonstrate that PD-L1 blockade enhances CD8+ T cell recruitment to tumors and therapeutic efficacy of combination radiation–peposertib treatment. Taken together, this study reveals a previously unappreciated mechanism by which DNA DSB repair inhibition augments DNA damage-inducing therapy and demonstrates how that mechanism can be leveraged in therapeutic strategies.