Tumor Necrosis Factor Receptor–Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c‐Myc Gene Expression and Protein Stability

Abstract

The oncogene c‐Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c‐Myc is significantly up‐regulated by tumor necrosis factor receptor–associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/– mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63‐linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c‐Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c‐Myc. Second, the K63‐linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c‐Myc and promotes c‐Myc protein acetylation, which thereby enhances c‐Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70‐kDa–interacting protein–mediated c‐Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c‐Myc signaling is also primed in hepatitis B virus–transgenic mice, unveiling a critical role for a mechanism in inflammation–cancer transition. In clinical specimens, TRAF6 positively correlates with c‐Myc at both the mRNA and protein levels, and high TRAF6 and c‐Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c‐Myc to promote human hepatocarcinogenesis. Consistently, curbing c‐Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c‐Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c‐Myc signaling, with potential implications for HCC therapy.

TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host

“…In addition, the oncogenic role of TRAF6 in tumors has been widely reported. TRAF6 is abnormally highly expressed in multiple tumor tissues and modulates the malignant behavior of tumor cells (41)(42)(43)(44)(45)(46). Furthermore, mounting evidence has revealed that TRAF6 plays a critical role in the development and activation of lymphocytes and myeloid cells (42,47,48).…”

Zwint facilitates melanoma progression by promoting c‑Myc expression

“…Furthermore, Sachdeva et al (29) demonstrated that microRNA-145 can inhibit c-Myc expression at the post-transcriptional level. c-Myc expression is also regulated by acetylation and ubiquitination (30)(31)(32). However, the specific molecular mechanism underlying Zwint regulation of c-Myc expression remains unclear and requires further study.…”

Angelicin Shows Antitumor Effects On The Oral Squamous Cell Carcinoma By Negatively Regulating DUSP6-Mediated cMYC-MAPK Signaling Pathway

“…In addition, research reported that angelicin regulates LPS-induced in ammation by suppressing MAPK pathways [35]. c-MYC, an important downstream transcription factor of the MAPK signaling pathway, is a protooncogene with an abnormal expression related to many cancers [36][37][38][39][40][41][42]. It also has been reported that reducing c-MYC can inhibit OSCC [43,44].…”