Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial (SDHB) also known as iron-sulfur subunit of complex II (Ip) is a protein that in humans is encoded by the SDHB gene.
The succinate dehydrogenase (also called SDH or Complex II) protein complex catalyzes the oxidation of succinate (succinate + ubiquinone ⇒ fumarate + ubiquinol). SDHB is one of four protein subunits forming succinate dehydrogenase, the other three being SDHA, SDHC and SDHD. The SDHB subunit is connected to the SDHA subunit on the hydrophilic, catalytic end of the SDH complex. It is also connected to the SDHC/SDHD subunits on the hydrophobic end of the complex anchored in the mitochondrial membrane. The subunit is an iron-sulfur protein with three iron-sulfur clusters. It weighs 30 kDa.
SDHB mutations are found in an increasing number of neoplasms, most notably paragangliomas and pheochromocytomas (SDHB-PPGLs). SDHB-PPGLs are slow-growing tumors, but about 50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed.
This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs.
They performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin gamma-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs.
They defined an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years after. We also show that PCDHGC3 downregulation engages metastasis-initiating capabilities by promoting cell proliferation, migration and invasion.
This data provide the first map of the DNA methylome episignature specific to a SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify SDHB-mutated cancer patients at high risk of metastasis who might benefit from future targeted therapies 1).