CENPT prevents renal cell carcinoma against ferroptosis by enhancing the synthesis of glutathione.

Abstract

Cancer is characterized by chromosomal instability (CIN), which leads to tumor heterogeneity and other malignant features. CIN is caused by abnormal centromere and kinetochore function, which results in aneuploidy, rearrangements, and micronucleus production. Centromere and kinetochore gene misexpression plays a vital role in tumor progression. Here we show that Centromere Protein T (CENPT) is highly expressed in renal carcinoma (RCC) and promotes the tumor proliferation and metastasis of RCC. CENPT is found to be critical for regulating the glutathione (GSH) metabolism pathway because it interacts with γ-glutamyl-cysteine ligase catalytic subunit (GCLC), consequently reducing reactive oxygen species levels and inhibiting ferroptosis. Mechanistically, CENPT increases the catalytic activity of GCLC by directly binding to GCLC ∆213-424aa competitively with glutamate-cysteine ligase modifier subunit (GCLM), consequently induces the GSH synthesis. In turn, GSH increases CENPT expression via transcriptional regulation mediated by the transcription factor ATF2, forming a CENPT-GCLC-GSH feedback loop that enhances the pro-carcinogenic effect of this axis in RCC. Our study identifies CENPT a potential target for RCC via forming a CENPT-GCLC-GSH feedback loop to inhibit ferroptosis. This may support a promising treatment strategy for RCC.