DECR1 Human

What is the primary function of DECR1 in human metabolism?

DECR1 functions as the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs) in the mitochondrial β-oxidation pathway. It plays a crucial role in metabolizing PUFAs with conjugated double bonds, converting them into intermediates that can be further processed by other enzymes in the β-oxidation pathway . This metabolic process is essential for energy production from unsaturated fatty acids and represents an important facet of cellular bioenergetics.

How is DECR1 expression regulated at the transcriptional level?

DECR1 is notably regulated by hormone signaling, particularly by the androgen receptor (AR) which acts as a transcriptional repressor of DECR1. Research demonstrates that AR binds strongly to the DECR1 promoter in response to dihydrotestosterone (DHT) treatment . ChIP-seq data and site-specific ChIP-qPCR assays have confirmed direct binding of AR to the DECR1 promoter region in both cell lines and clinical specimens, establishing DECR1 as an AR-repressed gene . This negative regulation has significant implications for conditions where androgen signaling is perturbed, such as during androgen deprivation therapy.

Which experimental models are most appropriate for studying DECR1 function?

Multiple experimental models have proven effective for investigating DECR1:

Selection of appropriate models depends on the specific research question, with consideration for AR status when studying hormone-related regulation .

How does altered DECR1 expression impact cancer cell behavior?

DECR1 overexpression significantly promotes cancer cell survival and progression through multiple mechanisms:

• Cell viability and proliferation: DECR1 knockdown significantly attenuates PCa proliferation across multiple cell lines, while overexpression enhances viability

• Colony formation capacity: Stable DECR1 overexpression enhances colony formation, while knockdown markedly decreases it

• 3D growth: DECR1 knockdown reduces growth in 3D spheroids, which better mimic in vivo conditions

• Cell migration: DECR1 knockdown reduces migration capability in multiple cell lines

• In vivo growth: DECR1 inhibition suppresses tumor cell proliferation and metastasis in mouse xenograft models

Notably, the effect on cancer cell viability is lost when cells are cultured in lipid-depleted media, confirming that the observed effects are specifically related to DECR1's role in fatty acid metabolism rather than non-specific cytotoxicity .

What is the mechanistic relationship between DECR1 and ferroptosis in cancer cells?

DECR1 serves as a protective factor against ferroptosis in cancer cells through its role in PUFA metabolism:

• DECR1 catalyzes the rate-limiting step in PUFA oxidation, preventing cellular accumulation of PUFAs

• When DECR1 is inhibited, PUFAs accumulate in the cell

• Accumulated PUFAs enhance mitochondrial oxidative stress

• This leads to increased lipid peroxidation

• Ultimately, the process triggers ferroptosis, a form of regulated cell death

This mechanism explains why DECR1 knockdown selectively affects cancer cells but not non-malignant prostate cells like PNT1, as cancer cells are often more dependent on altered metabolism and more vulnerable to ferroptotic cell death .

How might the inverse relationship between androgen receptor and DECR1 impact therapeutic strategies?

The negative regulation of DECR1 by AR has significant implications for prostate cancer therapy:

Since androgen deprivation therapy and AR antagonists increase DECR1 expression, combining these standard treatments with DECR1 inhibition could potentially overcome resistance mechanisms and enhance therapeutic efficacy in prostate cancer .

What are the most effective techniques for modulating DECR1 expression in experimental models?

Research has established several effective approaches for manipulating DECR1 expression:

RNA Interference:

• siRNA transfection: ON-TARGET plus siRNAs at 5 nM concentration using Lipofectamine RNAiMAX have demonstrated >80% knockdown efficiency

• Short hairpin vectors: For stable long-term knockdown studies

Gene Overexpression:

• Stable DECR1 overexpression significantly enhances cell viability and colony formation ability, providing a valuable tool for gain-of-function studies

In Vivo Modulation:

• Genetic approaches in mice

• Pharmacological inhibition using compounds like Atranorin and Kurarinone that bind to and inhibit DECR1

The selection of technique depends on experimental duration, desired level of knockdown, and specific research questions.

How can researchers effectively study AR regulation of DECR1?

Multiple complementary approaches have proven effective:

• Expression analysis after hormone manipulation:

  • qRT-PCR and western blot analysis following treatment with androgens (DHT) or AR antagonists (enzalutamide)

  • Include well-characterized AR target genes (KLK3, KLK2) as positive controls

• In vivo models:

  • Castration models to reduce androgen levels

  • Xenograft treatment with AR antagonists

• Clinical validation:

  • Patient-derived explants treated with enzalutamide

  • Analysis of clinical datasets for correlation between AR activity and DECR1 expression

• Chromatin interaction studies:

  • ChIP-seq to identify AR binding to the DECR1 promoter region

  • Site-specific ChIP-qPCR assays to confirm DHT-stimulated AR occupancy

This multi-faceted approach provides robust evidence for the regulatory relationship between AR and DECR1.

What methods are most appropriate for assessing DECR1's impact on fatty acid metabolism?

Several methodological approaches are recommended:

When designing these experiments, appropriate controls are essential, including non-targeted siRNAs and rescue experiments to confirm specificity of observed effects .

What is the emerging role of DECR1 in diabetic cardiomyopathy?

Recent research has uncovered an important role for DECR1 in diabetic cardiomyopathy (DCM):

• DECR1 is significantly upregulated in the hearts of diabetic rodents and in DCM mouse models across multiple genomic datasets

• Deletion of DECR1 in cardiomyocytes alleviates cardiac abnormalities in diabetes, while overexpression exacerbates DCM

• This suggests that DECR1 actively contributes to the pathogenesis of diabetic heart disease rather than being a passive biomarker

Understanding this role provides new insights into the metabolic dysregulation underlying diabetic heart disease and potential therapeutic approaches.

What is the molecular mechanism by which DECR1 contributes to cardiac damage?

DECR1 appears to promote cardiac damage through a specific molecular cascade:

• DECR1 interacts with and upregulates PDK4 (pyruvate dehydrogenase kinase 4)

• This leads to phosphorylation and mitochondrial translocation of HDAC3 (histone deacetylase 3)

• HDAC3 promotes HADHA deacetylation (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase alpha subunit)

• HADHA deacetylation enhances mitochondrial fatty acid oxidation (FAO)

• Increased FAO contributes to myocardial injury in diabetic cardiomyopathy

This pathway represents a novel mechanism linking altered fatty acid metabolism to cardiac damage in diabetic hearts and identifies multiple potential intervention points.

What therapeutic compounds targeting DECR1 show promise in cardiovascular disease models?

Drug screening efforts have identified two promising compounds:

These compounds represent potential therapeutic agents for treating DCM by targeting the DECR1-mediated pathway of enhanced mitochondrial fatty acid oxidation and subsequent cardiac damage .

How might DECR1 expression serve as a prognostic biomarker in cancer?

DECR1 shows promise as a prognostic biomarker in prostate cancer:

These findings suggest that DECR1 expression analysis could help identify patients at higher risk of aggressive disease progression and poor outcomes, potentially guiding treatment decisions.

What combination therapy approaches involving DECR1 inhibition warrant investigation?

Several combination approaches merit further research:

• DECR1 inhibition + AR antagonists: Since DECR1 is negatively regulated by AR, its expression increases during AR antagonist treatment. Combining DECR1 inhibition with enzalutamide or other AR-targeting drugs might enhance efficacy and overcome resistance .

• DECR1 inhibition + ferroptosis inducers: As DECR1 inhibition promotes ferroptosis, combination with other agents that induce or sensitize to ferroptosis could produce synergistic effects.

• DECR1 inhibition + metabolic therapies: Combining DECR1 inhibition with other metabolic interventions targeting glucose metabolism or alternative fatty acid pathways could comprehensively disrupt cancer cell metabolism.

• Cardiac applications: In heart disease, combining DECR1 inhibitors (such as Atranorin or Kurarinone) with standard treatments for diabetic cardiomyopathy might provide enhanced cardioprotection .

What methodological challenges need to be addressed in future DECR1 research?

Several key challenges require attention:

• Specificity of inhibition: Developing highly selective DECR1 inhibitors that don't affect related metabolic enzymes.

• Tissue-specific targeting: Given DECR1's role in normal metabolism, strategies for delivering inhibitors specifically to cancer cells or affected cardiac tissue.

• Biomarkers of response: Identification of markers that predict which patients will respond to DECR1-targeted therapies.

• Resistance mechanisms: Understanding potential compensatory pathways that might emerge after DECR1 inhibition.

• Translation to diverse cancer types: While much research has focused on prostate cancer, investigation of DECR1's role in other malignancies, particularly other hormone-dependent cancers that show DECR1 copy gain .

Addressing these challenges will be essential for translating the promising basic science findings on DECR1 into effective clinical applications.