Reversible Downregulation of MYC in a Spheroid Model of Metastatic Epithelial Ovarian Cancer

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2024 Nov 21

PMID 39572849

Authors

Adrian Buensuceso

Matthew J Borrelli

Yudith Ramos Valdes

Trevor G Shepherd

Affiliations

Soon will be listed here.

Abstract

Upon detachment from the primary tumour, epithelial ovarian cancer cells can form multicellular aggregates, also referred to as spheroids, that have the capacity to establish metastases at distant sites. These structures exhibit numerous adaptations that may facilitate metastatic transit and promote tumorigenic potential. One such adaptation is the acquisition of dormancy, characterized by decreased proliferation and molecular features of quiescence. One of the most frequently dysregulated genes in cancer is MYC, which encodes a transcription factor that promotes cell proliferation. In this study, we demonstrate that MYC protein abundance and associated gene expression is significantly decreased in EOC spheroids compared to adherent cells. This downregulation occurs rapidly upon cell detachment and is proteasome-dependent. Moreover, MYC protein abundance and associated gene expression is restored upon spheroid reattachment to an adherent culture surface. Overall, our findings suggest that suppression of MYC activity is a common feature of EOC spheroids and may contribute to the reversible acquisition of dormancy.

References

Conacci-Sorrell M, McFerrin L, Eisenman R . An overview of MYC and its interactome. Cold Spring Harb Perspect Med. 2014; 4(1):a014357. PMC: 3869278. DOI: 10.1101/cshperspect.a014357. View

Semenza G . The Genomics and Genetics of Oxygen Homeostasis. Annu Rev Genomics Hum Genet. 2020; 21:183-204. DOI: 10.1146/annurev-genom-111119-073356. View

OHara A, Bell D . The genomics and genetics of endometrial cancer. Adv Genomics Genet. 2012; 2012(2):33-47. PMC: 3415201. DOI: 10.2147/AGG.S28953. View

Daster S, Amatruda N, Calabrese D, Ivanek R, Turrini E, Droeser R . Induction of hypoxia and necrosis in multicellular tumor spheroids is associated with resistance to chemotherapy treatment. Oncotarget. 2016; 8(1):1725-1736. PMC: 5352092. DOI: 10.18632/oncotarget.13857. View

Xiao B, Sanders M, Underwood E, Heath R, Mayer F, Carmena D . Structure of mammalian AMPK and its regulation by ADP. Nature. 2011; 472(7342):230-3. PMC: 3078618. DOI: 10.1038/nature09932. View

Wiegand K, Shah S, Al-Agha O, Zhao Y, Tse K, Zeng T . ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med. 2010; 363(16):1532-43. PMC: 2976679. DOI: 10.1056/NEJMoa1008433. View

Amati B, Dalton S, Brooks M, Littlewood T, Evan G, Land H . Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max. Nature. 1992; 359(6394):423-6. DOI: 10.1038/359423a0. View

Benaud C, Dickson R . Regulation of the expression of c-Myc by beta1 integrins in epithelial cells. Oncogene. 2001; 20(6):759-68. DOI: 10.1038/sj.onc.1204152. View

Chen H, Liu H, Qing G . Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther. 2018; 3:5. PMC: 5837124. DOI: 10.1038/s41392-018-0008-7. View

10.

Wang H, Mannava S, Grachtchouk V, Zhuang D, Soengas M, Gudkov A . c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene. 2007; 27(13):1905-15. PMC: 3144565. DOI: 10.1038/sj.onc.1210823. View

11.

Tebay L, Robertson H, Durant S, Vitale S, Penning T, Dinkova-Kostova A . Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med. 2015; 88(Pt B):108-146. PMC: 4659505. DOI: 10.1016/j.freeradbiomed.2015.06.021. View

12.

Laski J, Singha B, Wang X, Valdes Y, Collins O, Shepherd T . Activated CAMKKβ-AMPK signaling promotes autophagy in a spheroid model of ovarian tumour metastasis. J Ovarian Res. 2020; 13(1):58. PMC: 7216359. DOI: 10.1186/s13048-020-00660-5. View

13.

Naska S, Park K, Hannigan G, Dedhar S, Miller F, Kaplan D . An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth. J Neurosci. 2006; 26(51):13344-56. PMC: 6674996. DOI: 10.1523/JNEUROSCI.4462-06.2006. View

14.

Huang L, Arany Z, Livingston D, BUNN H . Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996; 271(50):32253-9. DOI: 10.1074/jbc.271.50.32253. View

15.

Zhang P, Chen L, Zhou F, He Z, Wang G, Luo Y . NRP1 promotes prostate cancer progression via modulating EGFR-dependent AKT pathway activation. Cell Death Dis. 2023; 14(2):159. PMC: 9958327. DOI: 10.1038/s41419-023-05696-1. View

16.

Wang G, Jiang B, Rue E, Semenza G . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510-4. PMC: 41725. DOI: 10.1073/pnas.92.12.5510. View

17.

Ayantunde A, Parsons S . Pattern and prognostic factors in patients with malignant ascites: a retrospective study. Ann Oncol. 2007; 18(5):945-9. DOI: 10.1093/annonc/mdl499. View

18.

Boukouris A, Zhang Y, Saleme B, Kinnaird A, Zhao Y, Liu Y . A reversible metabolic stress-sensitive regulation of CRMP2A orchestrates EMT/stemness and increases metastatic potential in cancer. Cell Rep. 2022; 38(11):110511. DOI: 10.1016/j.celrep.2022.110511. View

19.

Burleson K, Casey R, Skubitz K, Pambuccian S, Oegema Jr T, Skubitz A . Ovarian carcinoma ascites spheroids adhere to extracellular matrix components and mesothelial cell monolayers. Gynecol Oncol. 2004; 93(1):170-81. DOI: 10.1016/j.ygyno.2003.12.034. View

20.

. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353):609-15. PMC: 3163504. DOI: 10.1038/nature10166. View