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
Pathria, Gaurav; Scott, David A; Feng, Yongmei et al. (2018) Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival. EMBO J 37:
García-Jiménez, Custodia; Goding, Colin R (2018) Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming. Cell Metab :
Theodosakis, Nicholas; Langdon, Casey G; Micevic, Goran et al. (2018) Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment-resistant melanoma, colorectal, and lung cancer. Pigment Cell Melanoma Res :
Senft, Daniela; Qi, Jianfei; Ronai, Ze'ev A (2018) Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18:69-88
Liu, Xiaoni; Zhang, Shang-Min; McGeary, Meaghan K et al. (2018) KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations. Mol Cancer Ther :
Wang, Jake; Perry, Curtis J; Meeth, Katrina et al. (2017) UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model. Pigment Cell Melanoma Res 30:428-435
Falletta, Paola; Sanchez-Del-Campo, Luis; Chauhan, Jagat et al. (2017) Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev 31:18-33
Theodosakis, Nicholas; Micevic, Goran; Langdon, Casey G et al. (2017) p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. J Invest Dermatol 137:2187-2196
Damsky, W E; Bosenberg, M (2017) Melanocytic nevi and melanoma: unraveling a complex relationship. Oncogene 36:5771-5792
Poothong, Juthakorn; Sopha, Pattarawut; Kaufman, Randal J et al. (2017) IRE1? nucleotide sequence cleavage specificity in the unfolded protein response. FEBS Lett 591:406-414

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