SDHC-related deficiency of SDH complex activity promotes growth and metastasis of hepatocellular carcinoma via ROS/NFκB signaling

Succinate dehydrogenase is a heterotetrameric complex comprising four nuclear-encoded subunits, catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle. A subset of cancers have been found to be associated with mutations in the four SDH genes. However, the functional roles of the SDH complex in tumorigenesis remain largely unclear, especially in hepatocellular carcinoma (HCC). Here, we investigated the expression levels of the four SDH subunits and their clinical significance in HCC, followed by systematic exploration of the effects of SDH dysfunction on HCC cell survival and metastasis both in vitro and in vivo, as well as the underlying molecular mechanisms. Our results showed that the expression of the SDHA/B/C/D subunits was significantly downregulated in HCC, associated with poor patient prognosis, and contributed to SDH inactivation. Additionally, attenuated SDH activity following SDHC knockdown promoted HCC-cell growth and metastasis both in vitro and in vivo via elevated reactive oxygen species levels and subsequent activation of nuclear factor-κB signaling. These findings suggest a critical tumor-suppressive role for SDH and provide strong evidence supporting this enzyme as a potential drug target in the treatment of HCC.