# Circular RNA hsa-circ-0001030 suppresses proliferation and cisplatin tolerance in TSCC via interaction with PKM2

## TL;DR

This study shows that a circular RNA called hsa-circ-0001030 helps fight tongue cancer by reducing tumor growth and cisplatin resistance through its interaction with PKM2.

## Contribution

The study identifies hsa-circ-0001030 as a novel tumor-suppressive circRNA that modulates cisplatin resistance and glycolytic metabolism in TSCC via PKM2.

## Key findings

- Hsa-circ-0001030 is downregulated in TSCC and cisplatin-resistant cells.
- Overexpression of hsa-circ-0001030 inhibits tumor growth and glycolytic flux while enhancing cisplatin sensitivity.
- Hsa-circ-0001030 binds to PKM2, inhibiting its enzymatic activity and glycolysis.

## Abstract

Aim: Cisplatin resistance remains a major obstacle to the effective treatment of tongue squamous cell carcinoma (TSCC). This study is dedicated to elucidating the role and mechanism of circular RNA (circRNA) hsa-circ-0001030 in modulating cisplatin sensitivity and metabolic reprogramming in TSCC.

Methods: CircRNA sequencing, quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization were used to test hsa-circ-0001030 expression in TSCC tissues and cell lines. Gain-of-function assays (colony formation, cell counting kit-8, Transwell assay, and xenograft models) were conducted to evaluate proliferation, invasion, and cisplatin response. Mechanistic studies, including RNA pull-down, RNA-binding protein immunoprecipitation, and western blotting, were performed to identify pyruvate kinase M2 (PKM2) as a binding partner of hsa-circ-0001030 and to assess glycolytic activity, glucose uptake, and lactate production.

Results: Hsa-circ-0001030 was markedly downregulated in TSCC and cisplatin-resistant cells. Overexpression of hsa-circ-0001030 suppressed tumor growth, migration, and glycolytic flux, while enhancing cisplatin sensitivity both in vitro and in vivo. Mechanistically, hsa-circ-0001030 directly bound to PKM2 at nucleotides 138-169, inhibited PKM2 enzymatic activity, restraining tetramer formation and increased tyrosine 105 (Tyr105) phosphorylation and thereby blocking PKM2-driven glycolysis. Clinically, low hsa-circ-0001030 expression correlated with advanced tumor-node-metastasis stage, poor differentiation, and unsatisfying prognosis in TSCC patients.

Conclusion: Hsa-circ-0001030 acted as a tumor-suppressive circRNA that might depress PKM2-dependent metabolic reprogramming and cisplatin resistance in TSCC, highlighting its potential as a prognostic biomarker and therapeutic target for overcoming chemoresistance.