The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer

Adamson, Beth; Brittain, Nicholas; Walker, Laura; Duncan, Ruaridh; Luzzi, Sara; Rescigno, Pasquale; Smith, Graham; McGill, Suzanne; Burchmore, Richard J.S.; Willmore, Elaine; Hickson, Ian; Robson, Craig N.; Bogdan, Denisa; Jimenez-Vacas, Juan M.; Paschalis, Alec; Welti, Jonathan; Yuan, Wei; McCracken, Stuart R.; Heer, Rakesh; Sharp, Adam; de Bono, Johann S.; Gaughan, Luke

doi:10.1172/jci169200

Cited by 4 publications

(7 citation statements)

References 65 publications

(126 reference statements)

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“…Interestingly, both our group and Adamson et al. 203 showed that DNA‐PKcs can regulate the RNA alternative splicing. 204 Aberrant androgen receptor (AR) signaling has proved to be the driver for prostate cancer (PC).…”

Section: Dna‐pkcs and Human Diseasesmentioning

confidence: 77%

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

Wu,

Song,

et al. 2024

MedComm

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The DNA‐dependent protein kinase (DNA‐PK), catalytic subunit, also known as DNA‐PKcs, is complexed with the heterodimer Ku70/Ku80 to form DNA‐PK holoenzyme, which is well recognized as initiator in the nonhomologous end joining (NHEJ) repair after double strand break (DSB). During NHEJ, DNA‐PKcs is essential for both DNA end processing and end joining. Besides its classical function in DSB repair, DNA‐PKcs also shows multifaceted functions in various biological activities such as class switch recombination (CSR) and variable (V) diversity (D) joining (J) recombination in B/T lymphocytes development, innate immunity through cGAS–STING pathway, transcription, alternative splicing, and so on, which are dependent on its function in NHEJ or not. Moreover, DNA‐PKcs deficiency has been proven to be related with human diseases such as neurological pathogenesis, cancer, immunological disorder, and so on through different mechanisms. Therefore, it is imperative to summarize the latest findings about DNA‐PKcs and diseases for better targeting DNA‐PKcs, which have shown efficacy in cancer treatment in preclinical models. Here, we discuss the multifaceted roles of DNA‐PKcs in human diseases, meanwhile, we discuss the progresses of DNA‐PKcs inhibitors and their potential in clinical trials. The most updated review about DNA‐PKcs will hopefully provide insights and ideas to understand DNA‐PKcs associated diseases.

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Section: Dna‐pkcs and Human Diseasesmentioning

confidence: 77%

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

Wu,

Song,

et al. 2024

MedComm

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“…FMR1 has been previously identified as a promoter of PCa progression via the m6A-mediated circRBM33-FMR1 complex and has also been found to be correlated with a poor prognosis in the disease-free survival of PCa patients [47]. RBMX is known to control AR transcript metabolism by monitoring the turnover, synthesis, and splicing of AR variants and has been found to be correlated with a high Gleason score in PCa patients [48]. In contrast to the above findings, our results indicated that higher expression of HNRNPC, FMR1, and RBMX may have a protective effect aiding the survival of mCRPC patients.…”

Section: Discussionmentioning

confidence: 99%

RNA m6a Methylation Regulator Expression in Castration-Resistant Prostate Cancer Progression and Its Genetic Associations

Liyanage,

Fernando,

Chamberlain

et al. 2024

Cancers

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N6-methyladenosine (m6A) methylation, a prevalent epitranscriptomic modification, plays a crucial role in regulating mRNA expression, stability, and translation in mammals. M6A regulators have gained attention for their potential implications in tumorigenesis and clinical applications, such as cancer diagnosis and therapeutics. The existing literature predominantly addresses m6A regulators in the context of primary prostate cancer (PCa). However, a notable gap in the knowledge emerges regarding the dynamic expression patterns of these regulators as PCa progresses towards the castration-resistant stage (CRPC). Employing sequential window acquisition of all theoretical mass spectra (SWATH-MS) and RNAseq analysis, we comprehensively profiled the expression of 27 m6A regulators in hormone/androgen-dependent and -independent PCa cell lines, revealing distinct clustering between tumor and adjacent normal prostate tissues. High-grade PCa tumors demonstrated the upregulation of METTL3, RBM15B, and HNRNAPA2B1 and the downregulation of ZC3H13, NUDT21, and FTO. Notably, we identified six m6A regulators associated with PCa survival. Additionally, association analysis of the PCa-associated risk loci in the cancer genome atlas program (TCGA) data unveiled genetic variations near the WTAP, HNRNPA2B1, and FTO genes as significant expression quantitative trait loci. In summary, our study unraveled abnormalities in m6A regulator expression in PCa progression, elucidating their association with PCa risk loci. Considering the heterogeneity within the PCa phenotypes and treatment responses, our findings suggest that prognostic stratification based on m6A regulator expression could enhance PCa diagnosis and prognosis.

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“…DNA-PK inhibition proved useful in re-sensitizing DU-145DxR PC cells to taxanes [137] and has been tested in combination therapy for mCRPC in a clinical trial (NCT02833883). However, given the additional role of DNA-PK in facilitating AR-mediated transcription [136,138], the prognostic and therapeutic value of DNA-PK in AR-independent PC remains uncertain.…”

Section: Dna Damage Repair (Ddr) Pathwaymentioning

confidence: 99%

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

Kouroukli,

Bravou,

Giannitsas

et al. 2024

Cancers

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Prostate cancer (PC) is a common malignancy among elderly men, characterized by great heterogeneity in its clinical course, ranging from an indolent to a highly aggressive disease. The aggressive variant of prostate cancer (AVPC) clinically shows an atypical pattern of disease progression, similar to that of small cell PC (SCPC), and also shares the chemo-responsiveness of SCPC. The term AVPC does not describe a specific histologic subtype of PC but rather the group of tumors that, irrespective of morphology, show an aggressive clinical course, dictated by androgen receptor (AR) indifference. AR indifference represents an adaptive response to androgen deprivation therapy (ADT), driven by epithelial plasticity, an inherent ability of tumor cells to adapt to their environment by changing their phenotypic characteristics in a bi-directional way. The molecular profile of AVPC entails combined alterations in the tumor suppressor genes retinoblastoma protein 1 (RB1), tumor protein 53 (TP53), and phosphatase and tensin homolog (PTEN). The understanding of the biologic heterogeneity of castration-resistant PC (CRPC) and the need to identify the subset of patients that would potentially benefit from specific therapies necessitate the development of prognostic and predictive biomarkers. This review aims to discuss the possible pathophysiologic mechanisms of AVPC development and the potential use of emerging tissue-based biomarkers in clinical practice.

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The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer

Cited by 4 publications

References 65 publications

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

The multifaceted functions of DNA‐PKcs: implications for the therapy of human diseases

RNA m6a Methylation Regulator Expression in Castration-Resistant Prostate Cancer Progression and Its Genetic Associations

Tissue-Based Diagnostic Biomarkers of Aggressive Variant Prostate Cancer: A Narrative Review

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