MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Kalogirou, Charis; Linxweiler, Johannes; Schmucker, Philipp; Snaebjornsson, Marteinn T.; Schmitz, W.; Wach, Sven; Krebs, Markus; Hartmann, Elena; Puhr, Martin; Müller, Andreas; Spahn, Martin; Seitz, Anna Katharina; Frank, Torsten; Marouf, Hecham; Büchel, Gabriele; Eckstein, Markus; Kübler, Hubert; Eilers, Marlies; Saar, Matthias; Junker, Kerstin; Roehrig, Florian; Kneitz, Burkhard; Rosenfeldt, Mathias T.; Schulze, Almut

doi:10.1038/s41467-021-25325-9

Cited by 51 publications

(51 citation statements)

References 58 publications

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“…Therefore, therapeutics that suppress elevated intratumoral cholesterol levels without induction of the feedback response are optimal strategies. Recently, drugs or compounds such as ezetimibe that target NPC1L1 protein for blocking cholesterol absorption and terbinafine that can inhibit SQLE were shown to be effective in inhibition of PCa tumor growth [9,21], thus supporting the notion that targeting the tumor aberrant cholesterol homeostasis can be an attractive option.…”

Section: Introductionmentioning

confidence: 95%

“…Notably, studies have demonstrated that both cholesterol biosynthesis and efflux are reprogrammed in mCRPC, which may be major contributors to tumor growth and lethal progression [6][7][8]. Indeed, elevated expression of cholesterol biosynthesis rate-limiting enzymes such as SQLE have been strongly correlated with poor outcome of PCa [7,9,10]. Low or loss of expression of key efflux proteins such as ABCA1 and metabolic enzymes such as CYP27A1 are also associated with the disease progression [6,11].…”

Section: Introductionmentioning

confidence: 99%

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Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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Metastatic castration-resistant prostate cancer (mCRPC) features high intratumoral cholesterol levels, due to aberrant regulation of cholesterol homeostasis. However, the underlying mechanisms are still poorly understood. The retinoid acid receptor-related orphan receptor gamma (RORγ), an attractive therapeutic target for cancer and autoimmune diseases, is strongly implicated in prostate cancer progression. We demonstrate in this study that in mCRPC cells and tumors, RORγ plays a crucial role in deregulation of cholesterol homeostasis. First, we found that RORγ activates the expression of key cholesterol biosynthesis proteins, including HMGCS1, HMGCR, and SQLE. Interestingly, we also found that RORγ inhibition induces cholesterol efflux gene program including ABCA1, ABCG1 and ApoA1. Our further studies revealed that liver X receptors (LXRα and LXRβ), the master regulators of cholesterol efflux pathway, mediate the function of RORγ in repression of cholesterol efflux. Finally, we demonstrated that RORγ antagonist in combination with statins has synergistic effect in killing mCRPC cells through blocking statin-induced feedback induction of cholesterol biosynthesis program and that the combination treatment also elicits stronger anti-tumor effects than either alone. Altogether, our work revealed that in mCRPC, RORγ contributes to aberrant cholesterol homeostasis by induction of cholesterol biosynthesis program and suppression of cholesterol efflux genes. Our findings support a therapeutic strategy of targeting RORγ alone or in combination with statin for effective treatment of mCRPC.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Yang

Huang

et al. 2022

Cancers

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“…Aberrant SM expression and activity is an emerging hallmark of numerous malignancies [21, 53], yet the contribution of the constitutively active trunSM to oncogenesis is unknown. Therefore, we performed immunoblotting of paired tumor and adjacent benign tissue lysates from cohorts of lean and obese endometrial cancer patients.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase

Coates

Olzomer

et al. 2022

Preprint

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Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-requiring enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show that hypoxia is the physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6, and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. Truncation of SM permits its localization to lipid droplets and is increased in hypoxic endometrial cancer tissues. These results uncover a feedforward mechanism that enables SM to accommodate fluctuations in substrate levels yet is also a likely contributor to its widely reported oncogenic properties.

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“…For example, VEGFR2 was shown to mark PCa cases with a high risk of progression ( 30 , 66 ). In addition, angiogenesis-related microRNAs such as let-7, miR-195 and miR-205 ( 67 ) are also deregulated and play prominent roles in PCa ( 68 – 70 ). However, no angiogenesis-specific inhibitor has met its clinical endpoint in phase III trials (see Figure 1A ).…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

2022

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Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature.

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MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Cited by 51 publications

References 58 publications

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase

Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside

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