Treatment-emergent neuroendocrine prostate cancer: molecularly driven clinical guidelines

An increasingly recognized mechanism of prostate cancer resistance is the transdifferentiation from adenocarcinoma to treatment-emergent neuroendocrine prostate cancer (t-NEPC), an extremely aggressive malignancy. The incidence of t-NEPC has been increasing in recent years, in part due to novel treatments that target the androgen receptor pathway. While clinicians historically had very few options for t-NEPC detection and treatment, recent research has uncovered key diagnostic tools and therapeutic targets that can be translated into improved patient care. In this article, we will outline the clinical features of t-NEPC and its molecular pathogenesis. Importantly, we will also discuss recently uncovered molecularly based strategies aimed at improving the diagnosis and treatment of t-NEPC. Finally, we will propose a unified algorithm that integrates clinical and molecular information for the clinical management of t-NEPC

EZH2 inhibition: a promising strategy to prevent cancer immune editing

Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells’ immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment

CUX1 transcription factor is required for optimal ATM/ATR-mediated responses to DNA damage

The p110 Cut homeobox 1 (CUX1) transcription factor regulates genes involved in DNA replication and chromosome segregation. Using a genome-wide-approach, we now demonstrate that CUX1 also modulates the constitutive expression of DNA damage response genes, including ones encoding ATM and ATR, as well as proteins involved in DNA damage-induced activation of, and signaling through, these kinases. Consistently, RNAi knockdown or genetic inactivation of CUX1 reduced ATM/ATR expression and negatively impacted hallmark protective responses mediated by ATM and ATR following exposure to ionizing radiation (IR) and UV, respectively. Specifically, abrogation of CUX1 strongly reduced ATM autophosphorylation after IR, in turn causing substantial decreases in (i) levels of phospho-Chk2 and p53, (ii) γ-H2AX and Rad51 DNA damage foci and (iii) the efficiency of DNA strand break repair. Similarly remarkable reductions in ATR-dependent responses, including phosphorylation of Chk1 and H2AX, were observed post-UV. Finally, multiple cell cycle checkpoints and clonogenic survival were compromised in CUX1 knockdown cells. Our results indicate that CUX1 regulates a transcriptional program that is necessary to mount an efficient response to mutagenic insult. Thus, CUX1 ensures not only the proper duplication and segregation of the genetic material, but also the preservation of its integrity

The non-coding transcriptome as a dynamic regulator of cancer metastasis.

Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms

Identification of the Polycomb protein CBX2 as a potential drug target in advanced prostate cancer and beyond

Globally, prostate cancer (PCa) represents the most commonly diagnosed cancer in men. While localized PCa can often be cured, all patients with metastatic disease inevitably develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). Increasing evidence suggests that epigenetic alterations involving the Polycomb Group (PcG) family drive PCa progression. Although the PcG protein CBX2 is required for prostate development, its implication in human cancer remains unexplored. I therefore hypothesized that CBX2 may become deregulated during PCa progression and induce transcriptional programs promoting PCa aggressiveness. Using patient-derived xenografts and clinical datasets, I have explored the epigenetic landscape of advanced PCa and identified the Polycomb Group protein and epigenetic reader CBX2 as a potential drug target. First, CBX2 was significantly up-regulated in metastatic and castration-resistant PCa tissues. Furthermore, CBX2 overexpression predicted lower overall survival and correlated with numerous adverse prognostic factors. In addition, CBX2 depletion induced proliferation arrest and apoptosis in metastatic PCa cell lines, implying that CBX2 is required for PCa cell survival. Microarray analysis conducted after CBX2 silencing revealed that CBX2 regulates many genes controlling cellular proliferation and differentiation. Given the rising incidence of NEPC in advanced PCa, I analyzed whether CBX2 was also involved in NEPC pathogenesis. Strikingly, CBX2 was consistently the most highly up-regulated epigenetic regulator across multiple clinical and xenograft tumor tissues. Furthermore, I derived a list of 185 genes down-regulated in NEPC that was preferentially enriched in PcG target genes and predicted poor clinical outcome, in line with a critical function for CBX2 in late-stage PCa. Since CBX2 has never been linked to human cancers, I conducted a comprehensive meta-analysis of CBX2 across many tumor types using previously published clinical data. Strikingly, these studies demonstrated that the CBX2 locus is rarely inactivated or down-regulated. In contrast, CBX2 was frequently amplified and over-expressed in many common tumors, where it correlated with metastatic dissemination and poor clinical outcome. Overall, this work identifies CBX2 as novel epigenetic driver of cancer progression and investigates the therapeutic potential of CBX2 in advanced solid malignancies.Medicine, Faculty ofGraduat

Histone modifications, stem cells and prostate cancer

Prostate cancer (PCa) is a very common neoplasm, which is generally treated by chemo-, radio-, and/or hormonal-therapy. After a variable time, PCa becomes resistant to conventional treatment, leading to patient death. Prostate tumor-initiating cells (TICs) and cancer repopulating cells (CRCs) are stem-like populations, driving respectively cancer initiation and progression. Histone modifiers (HMs) control gene expression in normal and cancer cells, thereby orchestrating key physiological and pathological processes. In particular, Polycomb group genes (PcGs) are a set of HMs crucial for lineage-specific gene silencing and stem cell self renewal. PcG products are organized into two main Polycomb Repressive Complexes (PRCs). At specific loci, PRC2 catalyzes histone H3 Lys27 trimethylation, which triggers gene silencing by recruiting PRC1, histone deacetylases and DNA methyl transferases. PRC1 catalyzes addition of the repressive mark histone H2A ubiquitination. Recently, the catalytic component of PRC1 (BMI1) was shown to play critical roles in prostate CRC self-renewal and resistance to chemotherapy, resulting in poorer prognosis. Similarly, pharmacological disruption of PRC2 by a small molecule inhibitor reduced the tumorigenicity and metastatic potential of prostate CRCs. Along with PcGs, some histone lysine demethylases (KDMs) are emerging as critical regulators of TIC/CRC biology. KDMs may be inhibited by specific small molecules, some of which display antitumor activity in PCa cells at micromolar concentrations. Since epigenetic gene regulation is crucial for stem cell biology, exploring the role of HMs in prostate cancer is a promising path that may lead to novel treatments

Elevated expression of a pharmacologic Polycomb signature predicts poor prognosis in gastric and breast cancer

Aim: Polycomb Group complexes are epigenetic repressors that silence tumor suppressive genes. Studies demonstrated that pharmacologic inhibition of Polycomb Group complexes with 3-deazaneplanocin A (DZNeP) induces cancer cell death by re-expressing silenced genes. Here we evaluate the prognostic significance of DZNeP target genes in gastric and breast cancer. Patients & methods/materials: The prognostic impact of a DZNeP-regulated gene signature was investigated using the KM Plotter and cBio Portal resources containing microarray data from tumor tissue. Results: We report that elevated expression of DZNeP targets is associated with poor clinical outcome in gastric and breast cancer. In gastric cancer, elevated expression of DZNeP signature is inversely correlated with decreased overall survival. In breast cancer, DZNeP signature predicted poor prognosis in HER2+ tumors but not in HER2- neoplasms. Conclusion: These findings demonstrate that DZNeP target genes are not predictive of better but rather of poor clinical outcome in gastric and breast cancer

Histone modifications, stem cells and prostate cancer

Prostate cancer (PCa) is a very common neoplasm, which is generally treated by chemo-, radio-, and/or hormonal-therapy. After a variable time, PCa becomes resistant to conventional treatment, leading to patient death. Prostate tumor-initiating cells (TICs) and cancer repopulating cells (CRCs) are stem-like populations, driving respectively cancer initiation and progression. Histone modifiers (HMs) control gene expression in normal and cancer cells, thereby orchestrating key physiological and pathological processes. In particular, Polycomb group genes (PcGs) are a set of HMs crucial for lineage-specific gene silencing and stem cell self renewal. PcG products are organized into two main Polycomb Repressive Complexes (PRCs). At specific loci, PRC2 catalyzes histone H3 Lys27 trimethylation, which triggers gene silencing by recruiting PRC1, histone deacetylases and DNA methyl transferases. PRC1 catalyzes addition of the repressive mark histone H2A ubiquitination. Recently, the catalytic component of PRC1 (BMI1) was shown to play critical roles in prostate CRC self-renewal and resistance to chemotherapy, resulting in poorer prognosis. Similarly, pharmacological disruption of PRC2 by a small molecule inhibitor reduced the tumorigenicity and metastatic potential of prostate CRCs. Along with PcGs, some histone lysine demethylases (KDMs) are emerging as critical regulators of TIC/CRC biology. KDMs may be inhibited by specific small molecules, some of which display antitumor activity in PCa cells at micromolar concentrations. Since epigenetic gene regulation is crucial for stem cell biology, exploring the role of HMs in prostate cancer is a promising path that may lead to novel treatments

The non-coding transcriptome as a dynamic regulator of cancer metastasis

Abstract Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms