Mepce Restrains Ferroptosis in Prostate Cancer Through 7SK-P-TEFb Pause Control

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Ferroptosis, a regulated cell death, can be induced by GPX4 inhibition.
• Understanding ferroptosis sensitivity in prostate cancer is crucial for developing new therapies.
• The precise mechanisms governing ferroptosis susceptibility in prostate cancer are not fully elucidated.

Purpose of the Study:

• To identify novel mechanisms and genetic factors that sensitize prostate cancer to ferroptosis.
• To investigate the role of MEPCE in regulating ferroptosis sensitivity.
• To explore the therapeutic potential of targeting the MEPCE-RN7SK-P-TEFb axis in prostate cancer.

Main Methods:

• Genome-wide CRISPR screening under graded GPX4 inhibition.
• Mechanistic perturbation-rescue experiments.
• Validation in prostate cancer xenograft and syngeneic models.

Main Results:

• MEPCE loss was identified as a conserved ferroptosis sensitizer in prostate cancer.
• MEPCE depletion destabilized RN7SK, disrupted the HEXIM1-P-TEFb complex, and promoted transcriptional elongation.
• This led to accelerated activation of a NRF2/ARE stress program, including HMOX1 induction, labile iron accumulation, and lipid peroxidation.
• MEPCE suppression impaired tumor growth and enhanced ferroptosis induction efficacy in vivo.

Conclusions:

• A novel transcriptional pause-control mechanism linking elongation dynamics to ferroptosis susceptibility was identified.
• The MEPCE-RN7SK-P-TEFb axis represents a potential therapeutic target for sensitizing prostate cancer to ferroptosis.