Howe, P. | Search bioRxiv

bioRxiv2026

TACC3-driven translation reprogramming dictates susceptibility or tolerance to mitotic stress

Translation reprogramming is central to cancer cell plasticity under stress. However, the molecular players coordinating translation and epitranscriptomic rewiring to determine adaptive responses to mitotic stress remain elusive. Here, we found that microtubule targeting agent (MTA)-induced CDK1 blocks global translation while it phosphorylates and degrades TACC3, a multifunctional adaptor, releasing eIF4A/eIF4E/eIF4G2 initiation factors. This promotes selective m7G cap-dependent translation of mRNAs with MTAup motif that are functionally required for apoptosis by disrupting proteostasis, promoting MTA-sensitivity. On the other hand, selectively translated TACC3 interacts with eIF3d/eIF4G1 and the m6A writer METTL3, mediating switch to m6A methylation and m7G cap-independent translation of mRNAs with hnRNPC-motif involved in chromosome segregation, driving MTA tolerance. TACC3 inhibition overcomes MTA resistance via restoring translation reprogramming. These findings demonstrate that TACC3 is a pivotal coordinator of translation/epitranscriptomic reprogramming and a therapeutic target in MTA-refractory cancers.

cancer biology↗

bioRxiv2020

Loss of CPAP expression promotes sustained EGFR signaling and Epithelial-Mesenchymal Transition in oral cancer cells

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck squamous cell carcinoma (HNSCC). Altered epidermal growth factor receptor (EGFR) levels can contribute to tumor metastasis and resistance to therapies. The epithelial-mesenchymal transition (EMT), by which epithelial cells acquire a mesenchymal and invasive phenotype, contributes significantly to tumor metastasis in OSCC, and EGFR signaling is known to promote this process. Microtubule inhibition therapies cause EGFR inactivation or increase the sensitivity to EGFR targeting drugs in various cancers including OSCC. In this study, using OSCC model, we show that loss of a microtubule/tubulin binding protein, centrosomal protein 4.1-associated protein (CPAP), which is critical for centriole biogenesis and normal functioning of centrosome, caused an increase in the EGFR levels and signaling and, enhanced the EMT features and invasiveness of OSCC cells. Further, depletion of CPAP increased the tumorigenicity of these cells in a xeno-transplant model. Importantly, CPAP loss-associated EMT features and invasiveness of multiple OSCC cells were attenuated upon depletion of EGFR in them. Overall, our novel observations suggest that in addition to its previously known regulatory role in centrosome biogenesis and function, CPAP plays an important role in suppressing EMT and tumorigenesis in OSCC by regulating EGFR homeostasis and signaling.

cancer biology↗