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Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated induction of ATF4. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether, our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.

Prostate cancer is highly prevalent, being the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of PTEN and SPRY2 (Sprouty 2) tumour suppressors, we identified enhanced creatine metabolism within the phosphagen system in progressive disease. Altered creatine metabolism was validated in in vitro and in vivo prostate cancer models and in clinical cases. Upregulated creatine levels were due to increased uptake through the SLC6A8 creatine transporter and de novo synthesis, resulting in enhanced cellular basal respiration. Treatment with cyclocreatine (a creatine analogue that potently and specifically blocks the phosphagen system) dramatically reduces creatine and phosphocreatine levels. Blockade of creatine biosynthesis by cyclocreatine leads to cellular accumulation of S-adenosyl methionine (SAM), an intermediary of creatine biosynthesis, and suppresses prostate cancer growth in vitro. Furthermore, cyclocreatine treatment impairs cancer progression in our GEMM and in a xenograft liver metastasis model. Hence, by targeting the phosphagen system, cyclocreatine results in anti-tumourigenic effects from both SAM accumulation and suppressed phosphagen system.

The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium., eLife digest The prostate is part of the reproductive organs in male mammals. Many of the cells lining the inside of the prostate – known as ‘luminal cells’ – need hormones to survive. Certain treatments for prostate cancer, including surgical and chemical castration, lead to fewer hormones reaching the prostate, which shrinks as luminal cells die. But some of these luminal cells are able to survive the damaging effects of castration, rebuilding the prostate upon treatment with hormones, which can lead to the cancer reappearing. It is unclear which type of luminal cells survive during periods without hormones and are responsible for regenerating the prostate. RUNX1 is a protein responsible for switching genes on and off, and is usually found in blood cells, which it helps to mature and perform their roles, but has also been detected in tissues that depend on hormones. Since the luminal cells of the prostate rely on hormones, could RUNX1 also be present in these cells? To answer this question, Mével et al. used mice to determine where and when RUNX1 is found in prostate cells. Mével et al. detected high levels of RUNX1 in a patch of luminal cells at the base of the prostate. Samples of these cells were taken for further testing from developing mouse embryos, healthy adult mice and mice in which the prostate was regenerating after surgical castration. Mével et al. found that these cells were a distinct subtype of luminal cells that were able to resist the effects of castration – they survived without hormones. Though these cells were present during the early stages of prostate embryonic development and in healthy adult prostate tissue, they were not responsible for rebuilding the prostate after castration. Mével et al.’s results indicate that, in mice, RUNX1 may act as a marker for a subset of luminal cells that can survive after castration. Further probing the roles of these castration-resistant luminal cells in normal and cancerous prostate tissue may improve the outcome of patients with prostate cancer treated with hormone deprivation therapy.

5-Aza-2'-deoxycytidine (5azadC) inhibits DNA methyltransferase and subsequently induces the expression of genes silenced by methylation. While treatment with 5azadC downregulated hTERT and upregulated MGMT expression in two glioma cell lines, there was no change in the expression of these two genes in the normal cell line. However, cell viability was reduced as a result of 5azadC treatment in all three cell lines. 5azadC treatment reduced telomerase expression and activity and subsequently enhanced chemosensitivity towards cisplatin, taxol and tamoxifen but not with the alkylating agents temozolomide (TMZ), carmustine and chlorambucil. To further evaluate the effect of these findings, the level of hTERT and MGMT expression was measured in a recurrent anaplastic ependymoma, seven glioblastoma and two normal brain tissues. While four of eight gliomas and one of the normal tissues expressed MGMT, hTERT was expressed in all gliomas but not in the normal brain tissue. Results of this study suggest that taxol together with 5azadC may be a good therapeutic combination for glioma. In addition, the work on cell lines can be repeated on tissues utilizing hTERT as the therapeutic target for demethylation using 5azadC in glioma.

Currently there is no cure for glioblastoma multiforme (GBM), and with chemotherapy compromised due to resistance, treatment of GBM is often difficult. Survival rates are generally poor, especially in older patients, this emphasizes the need for molecular targets designed to enhance efficiency of chemotherapy while limiting potential side effects. The development of combined therapy that ultimately incorporates molecular inhibition of immortalisation (telomerase), hsp90α, DNA repair (MGMT), EGFR, tumour suppressors, multi-drug resistance and cancer stem cell pathways is paramount to endeavour favourable innovative therapies, which in turn will help reduce the costs and ease the burden on health care.

Hsp90alpha's vital role in cell cycle progression and apoptosis together with its presence in gliomas and absence in normal tissue, make it a credible target for cancer therapy. Three sets of dsRNA oligos designed to align different regions of the hsp90alpha sequence were used to downregulate hsp90alpha. SiRNA 1, 2, and 3 resulted in significant levels of silencing of hsp90alpha after 48 hr treatment (p.0001). Concurrent treatment of the glioma cell line U87-MG with siRNA 1 and temozolomide (TMZ) resulted in a 13-fold reduction in the dose of TMZ required to achieve a similar effect if TMZ was used alone.

A novel co-transcription of CYP1A1 with hTERT, the active subunit of telomerase has been identified in alveolar epithelial cancer cell line (A549). This correlation was confirmed by chemically inducing the transcription of CYP1A1 in four cell lines: control normal lung cells (CCD-32Lu); alveolar epithelial cancer cell line (A549); large cell carcinoma (H460) and drug resistance large cell carcinoma (COR-L23/5010) observing a concomitant increase in hTERT mRNA level. In addition, siRNA was used to silence CYP1A1 transcription in A549 observing a decrease in the level of hTERT mRNA. The transcription correlation between CYP1A1 and hTERT may suggest a possible new mechanism for cancer therapy based on alternative gene targets. The co-transcription showed that the AhR pathway plays an active role in the activation of CYP1A1 which subsequently activates hTERT transcription. This study showed that the expression of CYP1A1 and CYP1A2 are cell specific and CYP2E1 and GSTM1 may not play a significant role in lung carcinogenesis.