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The role of APOBEC proteins in renal cell carcinoma

 

Kidney cancer is one of the most common cancer types affecting nearly 10.000 people in Germany every year. The most common type of kidney cancer is the clear cell renal cell carcinoma (ccRCC). While prognosis for low stage ccRCCs is quite favorable (60-80% 5-year-survival rate), metastatic ccRCC is characterized by very low survival rates. Since most RCCs are resistant to classical chemo- and radiotherapies, novel efficient therapies especially targeting metastasizing RCCs are needed.

 

 

We analyzed the molecular signature of RCC subtypes in TCGA data sets. Surprisingly, we found members of the APOBEC3 family of RNA-binding proteins (RBPs) to be significantly upregulated in ccRCCs. APOBEC3 proteins belong to a family of Zn-dependent cytidine deaminases. Primate APOBEC3 genes underwent gene duplication events that led to the diversification of this gene family with seven members in humans. We focused our research so far on the two family members APOBEC3C (A3C) and APOBEC3G (A3G). While their role as antiviral RBPs and editing enzymes has been well investigated in hematopoietic cells, there role in other cell types is poorly understood. APOBEC3 proteins were shown to associate with a variety of medium-sized ncRNAs (msRNAs) although the functional role of this has not been determined. Currently we are establishing RCC-derived cell lines either overexpressing A3C/G or that exhibit CRISPR/Cas9 mediated downregulation of both proteins. We expect that the modulation of APOBEC3 proteins significantly alters tumor cell properties in RCC-derived cell lines. Since the interferon pathway plays an important role in RCC progression and A3C/G are interferon responsive genes we aim at the further characterization of the role A3C/G in the modulation of this pathway. Since interferon alpha therapy is conducted for treatment of metastatic RCCs we also expect that our research will shed light on the role of this pathway on RCC progression and therapy.

 

 

APOBEC3-proteins – novel modulators of leukemic stem cell fate in acute myeloid leukemia

Leukemic stem cells (LSCs) are supposed to drive not only leukemogenesis but most importantly relapse in acute myeloid leukemia (AML). LSCs represent a low-frequency subpopulation of leukemia cells that possess stem cell properties distinct from the bulk leukemia cells, including self-renewal capacity, cell cycle quiescence and drug resistance. Furthermore, LSCs are functionally defined by their ability to engraft and initiate AML in a recipient mouse (initiation), to grow out after re-transplantation into secondary recipients (self-renewal) and preferable in tertiary recipients. Based on this assumed hierarchical model LSCs represent the apex, which continuously replenishes the AML bulk and thereby maintains AML and causes relapse. So far little is known about the molecular regulators that govern LSC-characteristics and biological functions.

 

APOBEC3 proteins belong to a family of Zn-dependent cytidine deaminases. We focused our research so far on the two family members APOBEC3C (A3C) and APOBEC3G (A3G) in renal cell carcinoma. Both proteins are cytoplasmic RBPs that are mainly expressed in the hematopoietic lineage. Especially the role of APOBEC3G as antiviral RNA-binding protein (RBP) and editing enzyme has been well investigated in hematopoietic cells upon HIV-infection. The cellular functions of the other family members including APOBEC3D (A3D) and APOBEC3F (A3F) remained largely elusive. Both proteins share a similar protein structure, which is characterized by two consecutive deaminase-domains that mediate RNA-association and presumably C-to-U-editing. Surprisingly, we found that A3C/G stabilize mRNAs in renal cancer cells, which are normally expressed in the hematopoietic lineage. Furthermore, we could so far not find any indication that A3C or A3G mediate their effects on target mRNAs by C-U-editing. These results indicate that APOBEC3 proteins might regulate hematopoietic target mRNAs by acting as stabilizing RBPs independent of their function as editing enzymes.