The traditional view of genome organization has been upended in the last decade with the discovery of vast amounts of non-protein-coding transcription. After initial concerns that this "dark matter" ...of the genome was transcriptional noise, it is apparent that a subset of these noncoding RNAs are functional. Long noncoding RNA (lncRNA) genes resemble protein-coding genes in several key aspects, and they have myriad molecular functions across many cellular pathways and processes, including oncogenic signaling. The number of lncRNA genes has recently been greatly expanded by our group to triple the number of protein-coding genes; therefore, lncRNAs are likely to play a role in many biological processes. Based on their large number and expression specificity in a variety of cancers, lncRNAs are likely to serve as the basis for many clinical applications in oncology.
Drugs targeting the cell cycle-regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor-positive breast cancer, and inhibitors targeting other ...cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets. SIGNIFICANCE: CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor-positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.
Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells ...from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial-mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ-ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for ...cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.
Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have clinical impact in a number of disease settings. In this Perspective, the mechanisms by which PARP1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP1 function into advances in disease management are reviewed.
Genomic alterations in DNA damage repair (DDR) genes other than
may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this ...hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-
DDR gene alterations.
TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline).
TRITON2 enrolled 78 patients with a non-
DDR gene alteration
(
= 49),
(
= 15),
(
= 12), and other DDR genes (
= 14). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in
2/19 (10.5%) and 2/49 (4.1%), respectively,
0/10 (0%) and 1/15 (6.7%), respectively, or
1/9 (11.1%) and 2/12 (16.7%), respectively, including no radiographic or PSA responses in 11 patients with confirmed biallelic
loss or 11 patients with
germline mutations. Responses were observed in patients with alterations in the DDR genes
, and
.
In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in
, or
. However, patients with alterations in other DDR-associated genes (e.g.,
) may benefit from PARP inhibition.
.
Using integrative genomic analysis of 360 metastatic castration-resistant prostate cancer (mCRPC) samples, we identified a novel subtype of prostate cancer typified by biallelic loss of CDK12 that is ...mutually exclusive with tumors driven by DNA repair deficiency, ETS fusions, and SPOP mutations. CDK12 loss is enriched in mCRPC relative to clinically localized disease and characterized by focal tandem duplications (FTDs) that lead to increased gene fusions and marked differential gene expression. FTDs associated with CDK12 loss result in highly recurrent gains at loci of genes involved in the cell cycle and DNA replication. CDK12 mutant cases are baseline diploid and do not exhibit DNA mutational signatures linked to defects in homologous recombination. CDK12 mutant cases are associated with elevated neoantigen burden ensuing from fusion-induced chimeric open reading frames and increased tumor T cell infiltration/clonal expansion. CDK12 inactivation thereby defines a distinct class of mCRPC that may benefit from immune checkpoint immunotherapy.
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•CDK12 biallelic inactivating mutations define a distinct subtype of prostate cancer•CDK12 loss is associated with genomic instability and focal tandem duplications•CDK12 loss leads to increased gene fusions, neoantigen burden, and T cell infiltration•Patients with CDK12 mutant tumors may benefit from immune checkpoint inhibition
Loss of both alleles of the CDK12 gene defines a molecular subtype of metastatic castration-resistant prostate cancer that is potentially targetable with immune checkpoint inhibitors.
Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. To delineate genome-wide lncRNA expression, we curated 7,256 RNA ...sequencing (RNA-seq) libraries from tumors, normal tissues and cell lines comprising over 43 Tb of sequence from 25 independent studies. We applied ab initio assembly methodology to this data set, yielding a consensus human transcriptome of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% were previously unannotated. About 1% (597) of the lncRNAs harbored ultraconserved elements, and 7% (3,900) overlapped disease-associated SNPs. To prioritize lineage-specific, disease-associated lncRNA expression, we employed non-parametric differential expression testing and nominated 7,942 lineage- or cancer-associated lncRNA genes. The lncRNA landscape characterized here may shed light on normal biology and cancer pathogenesis and may be valuable for future biomarker development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Prostate cancer is the second most common cause of cancer mortality among men in the United States. While many prostate cancers are indolent, an important subset of patients experiences disease ...recurrence after conventional therapy and progresses to castration-resistant prostate cancer （CRPC）, which is currently incurable. Thus, there is a critical need to identify biomarkers that will distinguish indolent from aggressive disease, as well as novel therapeutic targets for the prevention or treatment of CRPC. In recent years, long noncoding RNAs （IncRNAs） have emerged as an important class of biological molecules. LncRNAs are polyadenylated RNA species that share many similarities with protein-coding genes despite the fact that they are noncoding （not translated into proteins）. They are usually transcribed by RNA polymerase II and exhibit the same epigenetic signatures as protein-coding genes. LncRNAs have also been implicated in the development and progression of variety of cancers, including prostate cancer. While a large number of IncRNAs exhibit tissue- and cancer-specific expression, their utility as diagnostic and prognostic biomarkers is just starting to be explored. In this review, we highlight recent findings on the functional role and molecular mechanisms of IncRNAs in the progression of prostate cancer and evaluate their use as potential biomarkers and therapeutic targets.
Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated ...androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Forkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland
. FOXA1 is frequently mutated ...in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours
. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive
and oncogenic
roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.
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