Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Metabolism

Background:

• The enzyme IRE1α is constitutively active in various cancers, promoting tumor progression.
• IRE1α activation involves cleaving XBP1 mRNA to produce the XBP1s transcription factor and targeting other mRNAs via regulated IRE1α-dependent decay (RIDD).
• Emerging evidence suggests IRE1α plays a role in regulating lipid metabolism, but the specific contributions of XBP1s and RIDD are unclear.

Purpose of the Study:

• To investigate the roles of XBP1s and RIDD in IRE1α-mediated regulation of lipid metabolism.
• To explore the impact of IRE1α inhibition on lipid metabolism in triple-negative breast cancer cells.

Main Methods:

• Transcriptome and lipidome profiling of triple-negative breast cancer cells treated with an IRE1α inhibitor.
• Identification of RIDD targets using mRNA sequencing.
• Assessment of triacylglycerol accumulation and DGAT2 enzyme activity.
• Evaluation of cell sensitivity to nutritional stress and rescue experiments.

Main Results:

• IRE1α inhibition led to significant alterations in lipid metabolism genes and triacylglycerol (TAG) accumulation.
• DGAT2 mRNA, crucial for TAG biosynthesis, was identified as a RIDD target.
• Inhibition of IRE1α resulted in DGAT2-dependent TAG accumulation within lipid droplets.
• Cancer cells treated with IRE1α inhibitor showed increased sensitivity to nutritional stress, which was reversed by a DGAT2 inhibitor.

Conclusions:

• IRE1α's RIDD activity is critical for reprogramming cellular lipid metabolism in cancer.
• Targeting IRE1α influences TAG biosynthesis through DGAT2, affecting cancer cell adaptation to metabolic challenges.
• These findings highlight IRE1α as a potential therapeutic target for modulating lipid metabolism in cancer treatment.