GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma

Abstract

Background Aberrant TAK1 (transforming growth factor β‐activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab‐like GTPase activator and myotubularin domain containing 4) is a newly discovered p53‐independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). Results In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen‐activated protein kinase) and NF‐κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. Conclusions GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF‐κB signalling pathways.

TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling

“…Mechanistically, GRAMD4 inhibited HCC migration, invasion, and metastasis by promoting TAK1 degradation. 25 Recent research has demonstrated the clinical relevance of TAK1 in promoting HCC and sorafenib resistance. Combining TAK1 inhibitors with sorafenib inhibited the growth of sorafenib-resistant HCCLM3 xenografts in mouse models.…”

“…TAK1 deletions or losses can be detected in various types of human cancers and are positively associated with tumour progression and poor patient survival. [16] , [17] , [18] , [19] , [20] Elevated TAK1 expression and activity have also been detected in several human cancers, [21] , [22] , [23] , [24] including hepatocellular carcinoma (HCC), 25 , 26 indicating a dual role of TAK1 in regulating tumour initiation, progression, and metastasis. Mice with hepatocyte-specific deletions of TAK1 developed spontaneous liver fibrosis and hepatocarcinogenesis.…”

NUF2 Drives Cholangiocarcinoma Progression and Migration via Inhibiting Autophagic Degradation of TFR1

“…Nevertheless, the direct targets that mediated NUF2's biological actions in malignancies, particularly in CCA, were not well understood. In this study, we performed RNAseq and mass spectrometry analysis and identified TFR1 and MAPK which served as cancer promoting factors to promote the development of various tumors [38][39][40][41][42]. Therefore, we first explored the role of NUF2/ TFR1/MAPK axis in CCA.…”

Regulation of MAPK Signaling Pathways by the Large HERC Ubiquitin Ligases

“…Regarding the p38 pathway, ITCH acts inhibiting it, from one hand by targeting TXNIP for ubiquitin-dependent proteasome degradation, and from the other hand by catalyzing the K48-linked ubiquitylation and degradation of TAB1, a known activator of p38 [75,76]. In relation to the JNK pathway, ITCH has been described to regulate MKK4 ubiquitylation and subsequent degradation, thus decreasing JNK activation [77]. The HECT E3 ligases WWP1 and SMURF1 have also been related with the regulation of the three conventional MAPK signaling pathways ERK1/2, p38 and JNK.…”