2. Academic Validation
  3. A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression

A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression

  • Cancer Res. 2025 Sep 3. doi: 10.1158/0008-5472.CAN-24-2355.
Justin Chak Ting Cheung 1,  Lok Wan Ng 2,  Zhongxu Zhu 3,  Bonan Chen 4,  Stephen Li 5,  Mingjing Xu 1,  Xiaofan Ding 6,  Dandan Pu 1,  Yi Hu 7,  Yuqing Ren 8,  Wei Kang 1,  Ming Li 1,  Jason Wing Hon Wong 9,  Xin Wang 10,  Yuen Kit Cheng 11,  Wei Shen Aik 12,  Ka Leung Wong 13,  Simon Siu Man Ng 14,  Nathalie Wong 15,  Yujuan Dong 1
Affiliations

Affiliations

  • 1 Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 2 Hong Kong Baptist University, Hong Kong.
  • 3 Chinese Academy of Sciences, Hangzhou, China.
  • 4 Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China, Hong Kong, China.
  • 5 University of Hong Kong, Hong Kong, Hong Kong.
  • 6 University of Macau, Macau, China.
  • 7 First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
  • 8 University of Macau, Macau, Macau.
  • 9 University of Hong Kong, Pokfulam, Hong Kong.
  • 10 Chinese University of Hong Kong, Shatin, Hong Kong.
  • 11 Hong Kong Baptist University, Kowloon Tong, Hong Kong.
  • 12 Hong Kong Baptist University, Kowloon, Hong Kong.
  • 13 The Hong Kong Polytechnic University, Hong Kong.
  • 14 Chinese University of Hong Kong, Shatin, NT, Hong Kong.
  • 15 Chinese University of Hong Kong, Hong Kong, China.
PMID: 40900036 DOI: 10.1158/0008-5472.CAN-24-2355
Abstract

Metabolic reprogramming, notably alterations in the tricarboxylic acid (TCA) cycle, has emerged as a hallmark of Cancer that supports tumor growth and metastasis. Despite the TCA cycle being a classical central metabolic pathway, further exploration is needed to fully elucidate the intricate manifestations and contributory mechanisms of TCA cycle rewiring in colorectal carcinogenesis. Herein, we identified a splicing isoform of citrate synthase (CS), CS-ΔEx4, and unveiled its role in TCA cycle dysregulation in colorectal Cancer (CRC). CS-ΔEx4 was distinctly upregulated in CRC tumors compared with the canonical full-length (CS-FL) isoform. Clinical analyses established a strong correlation between elevated CS-ΔEx4 expression and Cancer recurrence as well as inferior survival outcomes in patients with CRC. Functional experiments revealed the active contribution of CS-ΔEx4 to the aggressive phenotype of CRC cells both in vitro and in vivo. Mechanistically, CS-ΔEx4 formed a heterocomplex with CS-FL within the mitochondria that influenced the enzymatic function of canonical CS and accelerated TCA cycle flux, thereby promoting accumulation of the oncometabolite 2-hydroxyglutarate. The CS-ΔEx4-mediated metabolic alterations engendered epigenomic modulations that drove the upregulation of oncogenic gene signatures. In silico screening identified a small molecule with potent anti-proliferative effects in CRC cell line and Organoid models that selectively antagonized the CS-ΔEx4 and CS-FL heterocomplex activity while sparing the CS-FL homodimers. Together, this study discovered the presence of a spliced CS isoform that promotes CRC progression and identified a molecule that holds potential for targeting the CS-ΔEx4 and CS-FL heterocomplex.

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