Inactivation of TACC2 epigenetically represses CDKN1A and confers sensitivity to CDK inhibitors
Zhi-Rui Lin1, Tian-Liang Xia2, Meng-Yao Wang3
1State 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.
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.
Insights
Loss of TACC2 in esophageal squamous cell carcinoma (ESCC) promotes tumor growth and predicts poor prognosis. Targeting TACC2 deficiency with CDK inhibitors offers a synthetic lethality strategy for ESCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Esophageal squamous cell carcinoma (ESCC) genomic landscape is known, yet actionable therapeutic targets are lacking.
- Identifying novel tumor suppressor genes is crucial for developing effective ESCC treatments.
Purpose of the Study:
- To identify potential tumor suppressor genes in ESCC through integrative genomic analysis.
- To explore the function and therapeutic potential of the candidate gene TACC2 in ESCC.
Main Methods:
- Genome-wide loss of heterozygosity and expression analysis to identify tumor suppressor genes.
- In vitro and in vivo functional studies of TACC2 in ESCC models.
- Investigating TACC2's interaction with NuRD and CoREST complexes and its role in epigenetic regulation.
Main Results:
- TACC2 inactivation, via copy loss and hypermethylation, correlates with poor ESCC prognosis.
- TACC2 depletion promotes ESCC tumorigenesis and progression in mouse models and cell lines.
- TACC2 loss leads to nuclear translocation of NuRD/CoREST components, repressing CDKN1A and elevating CDK1/2 activity.
- TACC2-deficient cells and organoids show increased sensitivity to CDK inhibitors like dinaciclib.
- Combined TACC2 inhibition and dinaciclib treatment significantly impairs ESCC tumor growth in vivo.
Conclusions:
- TACC2 functions as a tumor suppressor in ESCC.
- TACC2 deficiency creates a synthetic lethal vulnerability exploitable by CDK inhibitors.
- This study proposes a novel therapeutic strategy for ESCC based on synthetic lethality targeting TACC2.
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