24 Jan New Oncoprotein Offers Potential Therapeutic Target
MedicalResearch.com Interview with:
Dr. Hua Lu MS PhD
Department of Biochemistry & Molecular Biology
Reynolds and Ryan Families Chair in Translation Cancer
Tulane Cancer Center
Tulane University School of Medicine
New Orleans, Louisiana 70112
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: It has been well appreciated and acknowledged that p53 is the most important tumor suppressor in human body. However, approximately 50% of human cancers still sustain the wild type form of its gene, and also oddly, some cancers, such as breast cancer, which contain wild type p53, are often less sensitive to chemotherapy than those harbor mutated p53. Although a number of oncoproteins, including MDM2 and MDMX (MDM4), have been shown to be highly expressed and to inactivate p53 in those wild type p53-containing cancers, more molecules need to be discovered to keep p53 in control in order to let cancer cells to proliferate and growth.
Our study as described in our recent publication in Nature Communications unveils a new p53 target gene that encodes pleckstrin homology domain-containing protein (PHLDB3) as another p53 inhibitor in a negative feedback fashion. Interestingly and mechanistically, PHLDB3 can work with MDM2 by boosting its E3 ubiquitin ligase activity, consequently leading to degradation of p53. Biologically, PHLDB3 can promote cancer cell proliferation and growth in culture and in xenograft tumor models by in part inactivating p53 activity. More interestingly, PHLDB3 is highly amplified and expressed in a number of human cancers, such as pancreatic, prostate, colon and breast cancers. High expression of PHLDB3 is well correlated with the wild type status of p53 in certain portion of breast cancer. These findings uncover PHLDB3 as another oncoprotein that can promote cancer growth by partially inactivate p53, and thus might serve as a potential target for future development of anti-cancer therapy. Our study also suggests that PHLDB3 has a p53-independent function important for cancer growth.
MedicalResearch.com: What should readers take away from your report?
Response: This is the first study to reveal biological and biochemical functions of this oncoprotein as almost no study has ever been done on this protein. Also, it could be an important reason for why some cancers sustain wild type p53 and for drug resistance. Finally, it can be a good target for development of anti-cancer therapy in the future.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: In the near future, we will consolidate the oncogenic role of PHLDB3 dependently or independently of p53 by employing mouse model systems and examining more human cancer samples, such as breast, colon, lung, and pancreatic cancers. Also, we will dig out p53-independent molecular mechanisms underlying the oncogenic role of this protein. Finally, we will validate it as a potential drug target by performing the first two lines of research and testing if inactivating PHLDB3 might lead to anti-cancer potential in several cancer cells. Obviously, to fulfill these short term goals, we will need more research funds, as this study has not been funded thus far.
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Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53
Tengfei Chao, Xiang Zhou, Bo Cao, Peng Liao, Hongbing Liu, Yun Chen , Hee-Won Park, Shelya X. Zeng & Hua Lu
Nature Communications 7, Article number: 13755 (2016)
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