p53-responsive CMBL reprograms glucose metabolism and suppresses cancer development by destabilizing phosphofructokinase PFKP
Yingdan Huang,
Chen Xiong,
Chunmeng Wang,
Jun Deng,
Zhixiang Zuo,
Huijing Wu,
Jianping Xiong,
Xiaohua Wu,
Hua Lu,
Qian Hao,
Xiang Zhou
Affiliations
Yingdan Huang
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Lymphoma Medicine (Breast Cancer & Soft Tissue Tumor Medicine), Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
Chen Xiong
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
Chunmeng Wang
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Jun Deng
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
Zhixiang Zuo
State Key Laboratory of Oncology in South China, Cancer Center, Collaborative Innovation Center for Cancer Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou 510060, China
Huijing Wu
Department of Lymphoma Medicine (Breast Cancer & Soft Tissue Tumor Medicine), Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
Jianping Xiong
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
Xiaohua Wu
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
Hua Lu
Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
Qian Hao
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Corresponding author
Xiang Zhou
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Corresponding author
Summary: Aerobic glycolysis is critical for cancer progression and can be exploited in cancer therapy. Here, we report that the human carboxymethylenebutenolidase homolog (carboxymethylenebutenolidase-like [CMBL]) acts as a tumor suppressor by reprogramming glycolysis in colorectal cancer (CRC). The anti-cancer action of CMBL is mediated through its interactions with the E3 ubiquitin ligase TRIM25 and the glycolytic enzyme phosphofructokinase-1 platelet type (PFKP). Ectopic CMBL enhances TRIM25 binding to PFKP, leading to the ubiquitination and proteasomal degradation of PFKP. Interestingly, CMBL is transcriptionally activated by p53 in response to genotoxic stress, and p53 activation represses glycolysis by promoting PFKP degradation. Remarkably, CMBL deficiency, which impairs p53’s ability to inhibit glycolysis, makes tumors more sensitive to a combination therapy involving the glycolysis inhibitor 2-deoxyglucose. Taken together, our study demonstrates that CMBL suppresses CRC growth by inhibiting glycolysis and suggests a potential combination strategy for the treatment of CMBL-deficient CRC.
