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SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy

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SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Zhang, Huadi. 2017. SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061511 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy A dissertation presented by Huadi Zhang to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts August 2017 © 2017 Huadi Zhang All rights reserved. Dissertation Advisor: Professor David Pellman Huadi Zhang SPINT2 Suppresses Hippo Effector YAP and Limits Cellular Tolerance for Aneuploidy Abstract Oncogenic transformation is often accompanied by chromosome instability, an increased rate of chromosome missegregation. The consequent gain or loss of chromosomes—termed aneuploidy—hinders the growth of most non-cancerous tissues, but is prevalent in tumors. During tumorigenesis, aneuploidy contributes to cellular heterogeneity and may promote downstream mutations, including chromosome rearrangements and oncogene amplification. Cellular mechanisms that safeguard against aneuploidy remain unclear. The Hippo pathway is a tumor-suppressor mechanism with essential roles in regulating tissue homeostasis. YAP, the downstream effector inhibited by the Hippo pathway, is an oncogenic transcriptional cofactor that promotes proliferation and is frequently amplified in cancers. Upstream regulators of the Hippo pathway and YAP are partially understood. SPINT2 is a transmembrane protein with extracellular serine protease inhibitor domains and is a negative regulator of various proteases including activators of growth factors. Epigenetic silencing of SPINT2 by promoter hypermethylation is observed in cancers such as medulloblastoma, renal cell carcinoma, and acute myeloid leukemia. Notably, recent findings demonstrate that SPINT2 loss enables cells to tolerate multiple types of stress, including cytokinesis failure and DNA damage. Considering the distinct cellular machineries that respond to these stresses, it is conceivable that SPINT2 may regulate multiple signaling pathways. In the present dissertation, I delineate SPINT2’s role as a negative regulator of YAP. I demonstrate that SPINT2 limits YAP activity via protease-activated receptors. In addition, using iii models of chromosome missegregation and aneuploidy, I establish that loss of SPINT2 confers heightened cellular tolerance for aneuploidy. My findings highlight two intriguing hypotheses regarding cellular processes of cancer development. First, broad-spectrum membrane-anchored protease modulators such as SPINT2 may serve as “convergence points” where a multitude of extracellular signals are regulated for discrete downstream signaling events inside the cell. Second, the tolerance for aneuploidy may be a “built-in” component of oncogenic signaling such as YAP activation, as opposed to requiring separate cellular mechanisms. The aneuploid state of tumors, therefore, may be an integral output of intra- and extra-cellular oncogenic signaling, and may serve as a feedforward process that enhances further genomic instability during tumorigenesis. iv Table of Contents Abstract .......................................................................................................................................... iii Table of Contents ............................................................................................................................ v List of Figures and Tables............................................................................................................. vii Dedication and Acknowledgements .............................................................................................. ix Chapter 1 : Introduction .................................................................................................................. 1 1.1 Extracellular Proteolysis in Development and Disease......................................................... 4 1.1.1 Overview of extracellular proteases: regulation and signaling ...................................... 4 1.1.2 Protease-activated receptors (PARs) and G protein signaling ........................................ 8 1.1.3 Physiological functions of SPINT family protease inhibitors ...................................... 11 1.2 Regulation of the Hippo Pathway by Protease-Activated Receptors (PARs) ..................... 13 1.2.1 The Hippo pathway in tissue homeostasis and cancer development ............................ 13 1.2.2 Regulation of the Hippo pathway by GPCRs ............................................................... 17 1.3 Aneuploidy: A Hallmark of Cancer .................................................................................... 18 1.3.1 Causes and consequences of chromosome instability and aneuploidy ......................... 18 1.3.2 Cellular responses to aneuploidy .................................................................................. 20 1.4 Conclusion and Research Goals .......................................................................................... 24 Chapter 2 : Suppression of the Hippo Pathway Effector YAP by SPINT2 via Protease-Activated Receptors (PARs) and Associated G Proteins ........................................................................... 25 2.1 Introduction ......................................................................................................................... 26 2.2 Results ................................................................................................................................. 28 2.2.1 SPINT2 depletion results in YAP activation ................................................................ 28 2.2.2 SPINT2 regulates YAP via PAR1, PAR2, and Gi/o ...................................................... 35 2.2.3 SPINT2 inhibits PAR1 and PAR2 cleavage by endogenous proteases ........................ 40 2.2.4 SPINT2 loss is insufficient for anchorage-independent growth ................................... 42 2.3 Discussion ........................................................................................................................... 44 2.3.1 SPINT2 as a dual-function tumor suppressor limiting growth factors and YAP ......... 44 2.3.2 Potential mechanisms linking PAR1/2 and YAP ......................................................... 47 2.3.3 Which proteases may be involved? .............................................................................. 49 2.3.4 SPINT2 in the tumor microenvironment ...................................................................... 50 2.4 Materials and Methods ........................................................................................................ 53 2.5 Chapter Contributions ......................................................................................................... 63 v Chapter 3 : Elevation of Cellular Tolerance for Aneuploidy Following SPINT2 Depletion ....... 64 3.1 Introduction ......................................................................................................................... 65 3.2 Results ................................................................................................................................. 67 3.2.1 SPINT2 is epigenetically silenced in aneuploid cells ................................................... 67 3.2.2 SPINT2 depletion confers heightened tolerance for aneuploidy .................................. 73 3.2.3 Relevance and potential mechanisms of SPINT2 loss-induced aneuploidy tolerance . 79 3.3 Discussion ........................................................................................................................... 84 3.3.1 SPINT2, a pleiotropic suppressor of aneuploidy? ........................................................ 84 3.3.2 Connecting YAP activation and aneuploidy tolerance ................................................. 87 3.4 Materials and Methods ........................................................................................................ 90 3.5 Chapter Contributions ......................................................................................................... 96 Chapter 4 : Modulation of Acute Myeloid Leukemia (AML) Differentiation by ZEB2 .............. 97 4.1 Introduction ......................................................................................................................... 98 4.1.1 Hematopoiesis, leukemia, and AML ............................................................................ 98 4.1.2 Physiological functions of ZEB2 ................................................................................ 100 4.1.3 Measuring differentiation in AML ............................................................................. 101 4.1.4 Project rationale and significance ............................................................................... 102
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