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Clinical Data Investigation Identifies MARK3 as an Oncogenic Driver in Castration-Resistant Prostate Cancer

ABSTRACT: Castration-resistant prostate cancer (CRPC) represents an aggressive and fatal form of prostate cancer that emerges following resistance to androgen deprivation therapy. Despite the availability of various drugs that can enhance the quality and prolong the survival of CRPC patients, resistance to these therapies is frequently observed, making the disease increasingly difficult to treat. Alterations in the expression of kinases and phosphatases are key drivers of CRPC and present potential targets for more effective treatments. In this study, we have performed a comprehensive transcriptomic analysis of ~359 normal and CRPC patient samples from the cancer genome atlas to identify the differentially expressed kinases and phosphatases. We shortlisted the candidate genes based on their differential expression profiles, associations with patient survival, Gleason scores, and their impact on the fitness of prostate cancer cell lines. Our in-silico analysis identified microtubule affinity-regulating kinase 3 (MARK3) as a novel CRPC driver that is upregulated in CRPC patients, correlates with poor survival outcomes, and affects the fitness of CRPC cells. Pharmacological inhibition of MARK3 using PCC0208017, a MARK3 inhibitor, leads to reduced cell viability and migratory potential, as well as cell cycle arrest at G1 phase. Additionally, RNA sequencing analysis of 22Rv1 cells treated with the MARK3 inhibitor revealed that MARK3 influences genes involved in androgen response, epithelial-mesenchymal transition, mTOR and Myc signalling, underscoring its pivotal role in CRPC progression. Taken together, our results establish MARK3 as a novel and promising therapeutic target in CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276660 | GEO | 2025/04/23

REPOSITORIES: GEO

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Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).

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Clinical Data Investigation Identifies MARK3 as an Oncogenic Driver in Castration-Resistant Prostate Cancer

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