Translational cancer research · 2026
The m6A/METTL3 modifies USP11 to promote Warburg effect progression of colon cancer undifferentiated by HIF-1α/YAP signaling pathway.
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Wang Yingying, Zhu Feifei, Chen Xiaolei, Feng Lei, Pu Zhichen
Аннотация
BACKGROUND: In China, colorectal cancer (CLC) is the third most common malignancy, following lung cancer and thyroid cancer. This study attempts to reveal the protective mechanism of ubiquitin-specific peptidase 11 (USP11) on Warburg effect of CLC.
METHODS: The study used single-cell analysis and the Chinese Glioma Genome Atlas (CGGA) dataset. HCT-116 cells were transfected with the USP11 or small interfering (si)-USP11 plasmid, respectively.
RESULTS: The USP11 messengerRNA(mRNA) expression in patients with CLC was elevated compared to the normal group. Patients with high USP11 expression exhibited poorer survival than those with low USP11 expression in CLC. USP11 was expressed in the epithelial cells of CLC patients. USP11 promoted Warburg effect to induce cell growth progression of CLC. USP11 upregulates the expression of HIF-1α and YAP in CLC. Mechanistically, HIF-1α mediates the effect of USP11 in CLC by driving the progression of the Warburg effect. USP11 physically interacts with the HIF-1α complex and stabilizes HIF-1α protein in CLC cells via suppressing HIF-1α ubiquitination. Additionally, the N6-methyladenosine (m6A) methyltransferase METTL3 enhances USP11 stability in a YTHDF1-dependent manner.
CONCLUSIONS: This study demonstrates that the METTL3-mediated m6A modification facilitates USP11 stabilization by YTHDF1 in CLC models, providing novel mechanistic insights and potential therapeutic targets for the clinical management of CLC and other malignant tumors.
METHODS: The study used single-cell analysis and the Chinese Glioma Genome Atlas (CGGA) dataset. HCT-116 cells were transfected with the USP11 or small interfering (si)-USP11 plasmid, respectively.
RESULTS: The USP11 messengerRNA(mRNA) expression in patients with CLC was elevated compared to the normal group. Patients with high USP11 expression exhibited poorer survival than those with low USP11 expression in CLC. USP11 was expressed in the epithelial cells of CLC patients. USP11 promoted Warburg effect to induce cell growth progression of CLC. USP11 upregulates the expression of HIF-1α and YAP in CLC. Mechanistically, HIF-1α mediates the effect of USP11 in CLC by driving the progression of the Warburg effect. USP11 physically interacts with the HIF-1α complex and stabilizes HIF-1α protein in CLC cells via suppressing HIF-1α ubiquitination. Additionally, the N6-methyladenosine (m6A) methyltransferase METTL3 enhances USP11 stability in a YTHDF1-dependent manner.
CONCLUSIONS: This study demonstrates that the METTL3-mediated m6A modification facilitates USP11 stabilization by YTHDF1 in CLC models, providing novel mechanistic insights and potential therapeutic targets for the clinical management of CLC and other malignant tumors.