HPV E6/E7‐Induced Acetylation of a Peptide Encoded by a Long Non‐Coding RNA Inhibits Ferroptosis to Promote the Malignancy of Cervical Cancer

Abstract Although a fraction of functional peptides concealed within long non‐coding RNAs (lncRNAs) is identified, it remains unclear whether lncRNA‐encoded peptides are involved in the malignancy of cervical cancer (CC). Here, a 92‐amino acid peptide is discovered, which is named TUBORF, encoded by lncRNA TUBA3FP and highly expressed in CC tissues. TUBORF inhibits ferroptosis to promote the malignant proliferation of CC cells. Mechanistically, human papillomavirus (HPV) oncogenes E6 and E7 upregulate TUBORF through CREB‐binding protein (CBP)/E1A‐binding protein p300 (p300)‐mediated histone H3 lysine 27 acetylation (H3K27ac) of lncTUBA3FP enhancer. Furthermore, E6 and E7 elevate and recruit acetyltransferase establishment of sister chromatid cohesion N‐acetyltransferase 1 (ESCO1) to bind to and acetylate TUBORF, which facilitates the degradation of immunity‐related GTPase Q (IRGQ) via a ubiquitin‐proteasome pathway, resulting in the inhibition of ferroptosis and promotion of the malignant proliferation of CC cells. Importantly, silencing ESCO1 or TURORF amplifies anticancer effects by paclitaxel both in CC cells and in vivo. These novel findings reveal oncopeptide TUBORF and its acetyltransferase ESCO1 as important regulators of ferroptosis and tumorigenesis during cervical cancer pathogenesis and establish the scientific basis for targeting these molecules for treating CC.