2. Academic Validation
  3. Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors

Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors

  • Med. 2025 Jan 5:100568. doi: 10.1016/j.medj.2024.12.002.
Zhi-Rui Lin 1,  Tian-Liang Xia 2,  Meng-Yao Wang 3,  Lan-Jun Zhang 2,  Yan-Min Liu 2,  Bo-Yu Yuan 2,  Ai-Jun Zhou 2,  Li Yuan 2,  Jian Zheng 2,  Jin-Xin Bei 2,  Dong-Xin Lin 4,  Mu-Sheng Zeng 5,  Qian Zhong 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, P.R. China.
  • 2 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
  • 3 Radiation Oncology Department, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou 510245, P.R. China.
  • 4 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China; Department of Etiology and Carcinogenesis, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
  • 5 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: zengmsh@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China. Electronic address: zhongqian@sysucc.org.cn.
PMID: 39793578 DOI: 10.1016/j.medj.2024.12.002
Abstract

Background: The genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies.

Methods: Here, we perform integrative analysis of genome-wide loss of heterozygosity and expression to identify potential tumor suppressor genes. The functions and mechanisms of one of the candidates, TACC2, are then explored both in vitro and in vivo, leading to the proposal of a therapeutic strategy based on the concept of synthetic lethality.

Findings: We reveal that the inactivation of TACC2, due to copy number loss and promoter hypermethylation, is associated with poor prognosis in ESCC patients. TACC2 depletion enhances ESCC tumorigenesis and progression, as demonstrated in Tacc2 knockout mouse models and by increased growth abilities of ESCC cells. Mechanistically, TACC2 interacts with components of the NuRD and CoREST co-repressor complexes, including MTA1, MBD3, and HMG20B, in the cytoplasm. TACC2 loss leads to the translocation of these proteins into the nucleus, facilitating the formation of functional NuRD and CoREST complexes and the epigenetic repression of CDKN1A. This repression results in elevated CDK1/2 activation. Furthermore, TACC2-deficient cells and ESCC patient-derived organoids with reduced TACC2 expression show increased sensitivity to CDK inhibitors, particularly dinaciclib, which is currently in a phase III trial. Notably, the combination of TACC2-specific RNAi and dinaciclib in subcutaneous ESCC models significantly impairs tumor growth.

Conclusions: The findings suggest a strategy for Cancer treatment based on synthetic lethality.

Funding: Funded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP.

Keywords

CDK inhibitors; TACC2; Translation to humans; esophageal squamous cell carcinoma; loss of heterozygosity; synthetic lethality.

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