1. Academic Validation
  2. MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma

MTHFD2 Enhances cMYC O-GlcNAcylation to Promote Sunitinib Resistance in Renal Cell Carcinoma

  • Cancer Res. 2025 Mar 14;85(6):1113-1129. doi: 10.1158/0008-5472.CAN-24-0050.
Jinwen Liu # 1 Gaowei Huang # 1 2 Hao Lin # 3 Rui Yang # 1 Wenhao Zhan 1 Cheng Luo 1 Yukun Wu 1 Lingwu Chen 1 Xiaopeng Mao 1 Junxing Chen 1 Bin Huang 1
Affiliations

Affiliations

  • 1 Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
  • 3 Department of Urology, The Second Affiliated Hospital of Shantou University, Medical College, Shantou, China.
  • # Contributed equally.
Abstract

Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. In this study, we identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial Enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib-resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-N-acetylglucosamine (UDP-GlcNAc) biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and cyclin D1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance. Significance: MTHFD2 regulates cMYC O-GlcNAcylation to promote sunitinib resistance in renal cell carcinoma, highlighting the important role of one-carbon metabolism in sunitinib resistance and proposing therapeutic strategies to improve patient outcomes.

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