Marchf8, also known as membrane-associated ring-CH-type finger 8, is an E3 ubiquitin ligase. It plays a crucial role in multiple biological processes by regulating the stability of various proteins through ubiquitination. It is involved in pathways such as selective autophagy, apoptosis regulation, and antiviral defense, which are vital for maintaining cellular homeostasis and organismal health. Genetic models, like gene knockout mouse models, are valuable for studying its functions.

In HPV-positive head and neck cancer, MARCHF8 is upregulated by HPV. Knockdown of MARCHF8 in human HPV-positive HNC cells restores cell surface expression of TNFRSF death receptors and enhances apoptosis [1]. In mouse oral cancer cells expressing HPV16 E6 and E7, MARCHF8 knockout augments cancer cell apoptosis and suppresses tumor growth in vivo [1]. Also, in HPV-positive HNC cells, MARCHF8 stabilizes the HPV16 E7 protein by degrading CUL1 and UBE2L3, components of the ubiquitin ligase complex. MARCHF8 knockdown decreases the E7 protein level while increasing CUL1 and UBE2L3 levels, and overexpression of CUL1 and UBE2L3 suppresses tumor growth in vivo [2,3]. Moreover, in HPV-positive head and neck cancer, MARCHF8 knockout significantly suppresses tumor growth, increases the infiltration of NK and T cells in the tumor microenvironment, and enhances the tumor-cell killing activity of CD8+ T cells. Combining Marchf8 knockout with anti-PD-1 treatment synergistically suppresses tumor growth in mice bearing ICI-refractory tumors [4].

In conclusion, Marchf8 is a key E3 ubiquitin ligase involved in regulating apoptosis, viral protein stability, and cancer cell immune evasion. Gene knockout mouse models have revealed its significance in HPV-related head and neck cancer, suggesting that targeting Marchf8 could be a potential strategy for treating such cancers.