This application by investigators at the Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, P.R. China, is submitted in response to PAR-14-080 'International Research in Infectious Diseases, including AIDS (R01)'. Along with HIV infection, KSHV and KS have emerged as an important health problem worldwide. The increase in incidence of KSHV-associated tumors in the HIV population is of international concern especially in under-developed countries, such as China. Studies towards the elucidation of the mechanism for KSHV-induced tumorigenesis will provide new therapeutic targets. In KS lesions, the majority of tumor cells are latently infected by KSHV and express viral proteins such as latency associated nuclear antigen (LANA), suggesting an essential role for viral latent infection in tumorigenesis. Using tandem affinity purification (TAP) technology, we identified Krppel associated box domain associated protein-1 (KAP1) as a novel LANA-binding protein. KAP1 functions as a transcriptional repressor and can change epigenetic state by recruiting histone deacetylase and methyltransferase complex. We previously showed that LANA recruited KAP1 to the RTA promoter region of the KSHV genome, which was involved in transcriptional repression of RTA by LANA. Since KAP1 is an important transcription corepressor, we hypothesize that LANA is capable of regulating global host gene expression through interaction with KAP1. In this project, we will determine whether and how LANA contributes to the pro-proliferative gene signature of KSHV infected cell by down-regulating expression of cellular tumor repressor genes. On the other hand, our previous studies showed that LANA up-regulated BMP-Smad1-Id signaling through sustained BMP-activated p-Smad1 in the nucleus and enhanced its loading on the promoter of BMP target gene Id. We showed that Id proteins were significantly up-regulated in KSHV transformed KMM cells and abundantly expressed in human KS lesions. Strikingly, genetic inhibition of the BMP-Smad1-Id pathway significantly blocked the oncogenic phenotype of KSHV-transformed cells in vitro and in vivo. Interestingly, Id proteins also play critical roles in angiogenesis both during embryogenesis and tumor formation. Thus, we proposed to determine whether LANA modulates BMP-Smad1-Id signaling to facilitate tumor angiogenesis, since abundant angiogenesis is the feature of KS and is the key factor for KS progress. Moreover, we will also determine how LANA regulates the termination process of BMP-induced p-Smad1 activation and the mechanisms by which of Id proteins contribute to angiogenic phenotype of KMM cells. Finally, we will use various BMP signaling inhibitors to evaluate their inhibition efficacy on the tumorigenicity and pro-angiogenic phenotype of KMM cells. Through our studies, we expect to reveal novel insights onto the versatile functions of LANA in KSHV-related malignancies.
KSHV is the etiological agent of Kaposi' Sarcoma (KS), which is one of the major malignancies in AIDS patients and common neoplasm in KSHV endemic region including Xinjiang China. In the proposed studies we will focus on the versatile function of LANA in KSHV-related tumorigenesis and angiogenesis. The results would provide unique and novel clues for targeted therapeutic development for treatment of KS disease.
