The role of YWHAG in metastatic cancer

Abstract

In accordance with the World Health Organisation, cancer is currently one of the leading causes of mortality worldwide, with an estimated 10 million deaths in 2020 alone. Most cancer-related mortality arises from metastasis, one of the hallmarks of cancer, yet it remains poorly understood. Furthermore, resistance to therapy and relapse are common challenges that clinicians and patients face, suggesting that intercepting and possibly reversing metastasis might offer a potentially novel strategy. Our present study deciphered the regulome of oncogenic adaptor protein 14-3-3γ, otherwise also known as tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG), during epithelial-mesenchymal transition (EMT) and demonstrated that 14-3-3γ is a key player in the signalling network in cancer cells during the transition. Ablation of YWHAG results in the collapse of this network, hence intercepting metastasis and exposing the cancer cells to oxidative catastrophe, resulting in increased cell death. An integrative transcriptomic analysis substantiated by an unbiased kinase inhibitor screen predicts a modulatory role of YWHAG on tyrosine kinase and AGC families to regulate stress response and metabolic process during EMT. Further analysis revealed that a YWHAG-dependent cytoprotective mechanism, macroautophagy, is embedded in EMT-associated networks, protecting cancer cells from oxidative catastrophe as a result of enhanced metabolism to meet the energy demands needed for metastasis. Clinical tumour biopsies and our in vivo models further strengthen the higher autophagic flux and overexpression of YWHAG in metastatic tumours compared to primary tumours. However, inducible YWHAG knockdown in vivo models revealed reduced tumour volume and abolished metastasis. Taken together, network perturbation through the disruption of the YWHAG regulome and coordination might present a novel therapeutic strategy to curb tumour metastasis.