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

Context and significanceEsophageal cancer is one of the most common and deadly cancer types worldwide. However, unfortunately, no effective targeted therapy is part of the current treatments of esophageal cancer, especially for the major histological subtype of esophageal squamous cell carcinoma (ESCC). Here, Lin et al. reveal that TACC2 functions as a tumor suppressor in ESCC and that TACC2 is a useful biomarker to predict the prognosis of ESCC patients and the sensitivity of CDK inhibitors. Additionally, the authors demonstrate a synthetic lethal interaction between CDKs and TACC2 inactivation across multiple cancer types. These findings highlight the therapeutic potential of CDK inhibitors in cancer patients with TACC2 inactivation.Highlights•TACC2 functions as a tumor suppressor by the epigenetic regulation of p21•TACC2-NuRD/CoREST-p21 axis regulates the ESCC progression•TACC2 is a useful biomarker for guiding treatment using CDK inhibitors•Synthetic lethal interaction between CDKs and TACC2 inactivationSummaryBackgroundThe genomic landscape of esophageal squamous cell carcinoma (ESCC) has been characterized extensively, but there remains a significant need for actionable targets and effective therapies.MethodsHere, 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.FindingsWe 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.ConclusionsThe findings suggest a strategy for cancer treatment based on synthetic lethality.FundingFunded by NKRDP, NSFC, GDIIET, GDBABRF, GDECISTP, and SYSUTP.Graphical abstract