TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance

Abstract

The study unravels the clinical significance of TAK1 in HCC and sorafenib resistance. We identified a novel E3 ubiquitin ligase, FBXW2, targeting TAK1 for degradation, and MTDH contributes to TAK1 up-regulation through binding to FBXW2 mRNA and accelerates its degradation.

A Novel atTAK Against Hepatocellular Carcinoma: Overcoming Resistance to Sorafenib

“… 8 Moreover, potent proangiogenic factors such as interleukin 8 are among the genes most significantly regulated by TAK1 in cancer. 9 This evidence strengthens the relevance of the findings by Xia et al 4 on the role of TAK1 in the resistance to agents with a strong antiangiogenic activity such as sorafenib.…”

“…Collectively, the findings presented by Xia et al 4 pave the path for the development of novel therapies against sorafenib-resistant HCC. Because of its crucial role in different physiological processes including inflammation and immune system homeostasis, the direct targeting of the kinase function of TAK1 poses critical challenges for the development of selective inhibitors that could be responsible for unbearable side effects.…”

“…In the current issue of Cellular and Molecular Gastroenterology and Hepatology , Xia et al 4 contribute to this field significantly by describing the role performed by the transforming growth factor-β–activated kinase 1 (TAK1) in driving HCC progression and promoting the acquisition of resistance to sorafenib. TAK1 is a serine/threonine kinase that integrates inputs from several receptors for proinflammatory signaling, including transforming growth factor-β, interleukin 1, and tumor necrosis factor-α, to regulate transcription factors involved in the protection from apoptosis and stemness, including nuclear factor-κB, Activator protein 1, and Yes Associated Protein/transcriptional coactivator with a PDZ binding domain.…”

“…K48-linked ubiquitylation of TAK1 blocks TAK1 activation, 10 whereas, K63-linked ubiquitylation of TAK1 sustains its kinase activity in part by allowing its interaction with the TAK1-binding adaptor proteins, resulting in TAK1 autophosphorylation and full enzymatic activation, but also by preventing its proteasome-dependent degradation. 11 In their study, Xia et al 4 identified FBWX2-mediated K48-linked ubiquitylation as a novel mechanism controlling TAK1 protein stability. Xia et al 4 showed in sorafenib-resistant HCC how FBWX2 is degraded by the RNA-binding protein metadherin, which is a prognostic predictor of shorter disease-free survival in HCC patients and a well-known promoter of HCC metastasis.…”

“… 11 In their study, Xia et al 4 identified FBWX2-mediated K48-linked ubiquitylation as a novel mechanism controlling TAK1 protein stability. Xia et al 4 showed in sorafenib-resistant HCC how FBWX2 is degraded by the RNA-binding protein metadherin, which is a prognostic predictor of shorter disease-free survival in HCC patients and a well-known promoter of HCC metastasis. 4 TAK1 protein stabilization is a critical aspect in its signaling because modulation of several downstream targets such as Yes Associated Protein/transcriptional coactivator with a PDZ binding domain often relies on the expression of TAK1, rather than on its own kinase activity.…”