Understanding mechanisms underlying control of tumorigenesis and metastasis is central to development of means to intervene in these processes. Reports from three laboratories suggest that the Siah ubiquitin ligases (Siahl and Siah2) function in pancreatic, mammary, melanoma and prostate tumor development and/or progression. Our studies revealed the role of Siah2 in melanoma development and progression through its effect on HIF and Ras signaling pathways. By regulating prolyl hydroxylase 3 stability, Siah2 controls HIFIa availability and the ability of melanoma cells to metastasize, without affecting tumorigenicity. By regulating Sprouty2 (SPRY2) stability, Siah2 regulates Ras and Raf signaling pathways, which dictate melanoma tumorigenicity. Consistent with these findings, Siah2 expression increases in more mestastatic melanomas, as determined by analysis of melanoma TMA. These findings provide a rationale to investigate mechanisms underlying regulation and function of Siah2 in melanoma. Our initial observations also suggest that AKT regulates Siah2 transcription. We will delineate mechanisms underlying Akt-mediated increase of Siah2 expression in melanoma where 50% of tumors contain a constitutively active Akt. Collectively, our findings indicate that: (i) Siah2 expression is upregulated in malignant melanomas, (ii) Siah2 inhibition attenuates melanoma tumorigenicity through SPRY2-Ras signaling, (iii) Siah2 inhibition attenuates melanoma metastasis through PHD3-HIF signaling, and (iv) AKT regulates Siah2 expression. Together, these observations provide the foundation for our hypothesis that under the control of AKT signaling, Siahl/2 plays a central role In regulation of melanoma tumorigenesis and metastasis. To test this hypothesis we will use biochemistry, molecular biology, cell biology and mouse models to: (1) extend our original findings defining AKT-dependent mechanisms underlying regulation of Siah2 transcription, and (2) characterize Siah2-Sprouty2 interaction relevant to different stages of melanoma tumor development. We will also (3) utilize Tg-N-Ras/Alnk4a mice, which develop metastatic melanoma, to assess the role of Siah (following crosses with Siah1a'':Siah2"''and Siah2"'":Siah1a*'' mice) in melanoma development and progression. Additional studies addressing Siah2 activity in tumorigenesis and metastasis will be carried out in collaboration with Project 2 to identify metabolic pathways affected by Siah2 and with Project 3, which focuses on identification and characterization of Siah2 inhibitors. Collectively this project should provide new important information regarding the role of Siah2 in regulating melanoma tumorigenesis and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA128814-05
Application #
8528366
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$423,991
Indirect Cost
$206,559
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Placzek, Andon N; Prisco, Gonzalo Viana Di; Khatiwada, Sanjeev et al. (2016) eIF2α-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons. Elife 5:
Bai, Yongsheng; Kinne, Jeff; Donham, Brandon et al. (2016) Read-Split-Run: an improved bioinformatics pipeline for identification of genome-wide non-canonical spliced regions using RNA-Seq data. BMC Genomics 17 Suppl 7:503
Wang, Miao; Kaufman, Randal J (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326-35
Han, Jaeseok; Kaufman, Randal J (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57:1329-38
Feng, Yongmei; Pinkerton, Anthony B; Hulea, Laura et al. (2015) SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex. Cancer Res 75:5211-8
Jeon, Young Joo; Khelifa, Sihem; Ratnikov, Boris et al. (2015) Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 27:354-69
Qi, Jianfei; Ronai, Ze'ev A (2015) Dysregulation of ubiquitin ligases in cancer. Drug Resist Updat 23:1-11
Lau, E; Sedy, J; Sander, C et al. (2015) Transcriptional repression of IFNβ1 by ATF2 confers melanoma resistance to therapy. Oncogene 34:5739-48
Lau, Eric; Feng, Yongmei; Claps, Giuseppina et al. (2015) The transcription factor ATF2 promotes melanoma metastasis by suppressing protein fucosylation. Sci Signal 8:ra124
Senft, Daniela; Ronai, Ze'ev A (2015) UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem Sci 40:141-8

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