The research of this laboratory is currently focused on delineation of the signal transduction pathways that mediate tumor-suppressing defense mechanisms in mammals, using cell culture and animal models
Our studies in the last several years have demonstrated a novel role of the p38 MAPK pathway in tumor suppression. We found that by mediating oncogene-induced senescence, p38 and other signaling components in this pathway, including a p38 downstream substrate kinase PRAK and a multifunctional acetyltransferase Tip60, prevent oncogenic transformation in cells and inhibit cancer development in mouse models, and that some of these signaling components are also inactivated in human tumors and thus are bona fide tumor suppressors.
These studies have revealed for the first time a tumor suppressing function of the p38 MAPK pathway, which was previously recognized as a mediator of inflammation and stress responses, and have provided novel insights into the mechanisms and signaling pathways that mediate tumor suppression in mammals.
Results from our investigations will also potentially lead to development of new cancer therapies targeting oncogene-induced senescence and the p38 pathway. In addition, through functional screening of microRNA expression libraries, studies from this laboratory have identified oncogenic microRNAs that can disrupt oncogene-induced senescence, and have revealed the targets of these microRNAs involved in senescence disruption.
Further investigations indicated that different p38 isoforms mediate oncogene-induced senescence through different downstream effectors, with p38 stimulates p16INK4A expression, p38g phosphorylates and activates p53, and p38d mediates senescence through a p16INK4A- and p53-indendent mechanism. P38 was previously identified as a mediator of inflammation and stress responses.
Our findings have revealed a novel function of p38 in oncogene-induced senescence and tumor suppression, and have identified a new signaling pathway that mediates senescence.
Wang W, Chen X, Liao R, Deng Q, Zhou JJ, Huang S and Sun P, 2002. Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence. Mol. Cell Biol. 22:3389-3403.
Deng Q, Liao R, Wu BL and Sun P, 2004. High-intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J. Biol. Chem. 279:1050-9.
Kwong J, Hong L, Liao R, Deng Q, Han J and Sun P. 2009 p38α and p38γ Mediate oncogenic RAS-induced senescence through differential mechanisms. J. Biol.Chem. 284:11237-46. PMCID: PMC2670128
Kwong J, Chen M, Lv D, Luo N, Xiang R and Sun P. 2013. Induction of p38d expression plays an essential role in oncogenic ras-induced senescence. Mol. Cell. Biol. 33:3780-3794. PMCID: PMC3811880
These findings provided new insights into the signal transduction pathway that mediate oncogene-induced senescence, and demonstrated for the first time that the p38 pathway suppresses cancer development in vivo by mediating senescence.
To explore the mechanism that regulates the tumor suppressing function of PRAK, we perform a yeast 2 hybrid screen to search for PRAK interacting protein. This screen identified a histone acetyltransferase Tip60. We showed that like p38 and PRAK, Tip60 is also required for oncogene-induced senescence.
Further investigation revealed a posttranslational modification cascade involving p38, Tip60 and PRAK that mediates oncogene-induced senescence. Following activation by oncogenic ras, p38 induces the acetyltransferase activity and pro-senescent function of Tip60 by phosphorylating Tip60 at T158; and once activated, Tip60 in turn induces the protein kinase activity and the pro-senescent function of PRAK by acetylating PRAK at K364. Moreover, phosphorylation by p38 also stimulates the ability of Tip60 to acetylate and activate p53 and induce apoptosis in response to DNA damage.
These results revealed a novel pathway that mediates oncogene-induced senescence and DNA damage responses. We are currently investigating the mechanism by which Tip60-mediated acetylation promotes the enzymatic activity and biological function of PRAK.
Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong M, Frangou CG, Yates, JR III, Wright PE and Han J, 2007. PRAK Is Essential for ras-Induced Senescence and Tumor Suppression. Cell 128:295-308.
Yoshizuka N, Lai M, Liao R, Cook R, Xiao C, Han J, Sun P. 2012. PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway. Mol Cancer Res. Jun;10(6):810-20. Epub 2012 Jun 4 PMCID: PMC3378811
Zheng H, Seit-Nebi A, Han X, Aslanian A, Tat J, Liao R, Yates JR III, Sun P. 2013. A posttranslational modification cascade involving p38, Tip60 and PRAK mediates oncogene-induced senescence. Molecular Cell 50:699-710. PMCID:PMC3679363
Xu Y, Liao R, Li N, Xiang R, Sun P. 2014. Phosphorylation of Tip60 by p38α regulates p53-mediated PUMA induction and apoptosis in response to DNA damage. Oncotarget. 5:12555-72. PMCID: PMC4350347
One of the hits identified from this screen was the miR-17-92 cluster, a polycistron containing 6 miRNAs, which is frequently amplified or overexpressed in human cancers. Further dissection of the miRNA components in this cluster revealed that miR-17-92 disrupts senescence induction through its miR-17/20a seed family that targets p21WAF1, a key effect of senescence.
Taken together with the previous reports that miR-17-92 inhibits apoptosis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster promotes tumorigenesis by antagonizing both tumor suppressing mechanisms, apoptosis and senescence, through the activity of different miRNA components encoded in this cluster.
These findings provided a new mechanism underlying the oncogenic activity of miR-17-92. We are currently analyzing the other senescence-disrupting miRNAs identified from our screen.
Hong L, Lai M, Chen M, Xie C, Liao R, Kang YL, Xiao C, Hu W-Y, Han J, and Sun P. 2010. The miR-17-92 Cluster of microRNAs Confers Tumorigenicity by Inhibiting Oncogene-Induced Senescence. Cancer Res. 70:8547-57. Epub 2010 Sep 17. PMCID: PMC2970743
PRAK is activated by p38 in response to tumor secreted pro-angiogenic factors in host endothelial cells, where it mediates cell migration towards tumors and incorporation of these cells into the tumor vasculature.
These findings have uncovered a novel signaling circuit essential for endothelial cell motility and tumor angiogenesis, and, together with our previous studies, demonstrated that the tumor-suppressing and tumor-promoting functions of the p38-PRAK pathway are temporally and spatially separated during cancer development in vivo, depending on the stimulus, the tissue type and the stage of cancer development in which it is activated.
Our results indicated that PRAK is specifically required for tumor angiogenesis but not for normal angiogenesis, thus providing the basis for a potential therapeutic strategy for cancer by targeting PRAK-mediated tumor angiogenesis. This strategy is currently being evaluated in our lab.
Yoshizuka N, Chen RM, Xu Z, Liao R, Hong L, Hu W-Y, Yu G, Han J, Chen L, Sun P. 2012. A Novel Function of p38-Regulated/Activated Kinase (PRAK) In Endothelial Cell Migration and Tumor Angiogenesis. Mol Cell Biol. 32(3):606-18. 2012 Feb;32(3):606-18 Epub 2011 Nov 28. PMCID: PMC3266605