YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

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Abstract

Colorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

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Most cited references 27

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Colorectal cancer statistics, 2017.

Rebecca Siegel, Kimberly D Miller, Stacey Fedewa … (2017)

Colorectal cancer (CRC) is one of the most common malignancies in the United States. Every 3 years, the American Cancer Society provides an update of CRC incidence, survival, and mortality rates and trends. Incidence data through 2013 were provided by the Surveillance, Epidemiology, and End Results program, the National Program of Cancer Registries, and the North American Association of Central Cancer Registries. Mortality data through 2014 were provided by the National Center for Health Statistics. CRC incidence rates are highest in Alaska Natives and blacks and lowest in Asian/Pacific Islanders, and they are 30% to 40% higher in men than in women. Recent temporal patterns are generally similar by race and sex, but differ by age. Between 2000 and 2013, incidence rates in adults aged ≥50 years declined by 32%, with the drop largest for distal tumors in people aged ≥65 years (incidence rate ratio [IRR], 0.50; 95% confidence interval [95% CI], 0.48-0.52) and smallest for rectal tumors in ages 50 to 64 years (male IRR, 0.91; 95% CI, 0.85-0.96; female IRR, 1.00; 95% CI, 0.93-1.08). Overall CRC incidence in individuals ages ≥50 years declined from 2009 to 2013 in every state except Arkansas, with the decrease exceeding 5% annually in 7 states; however, rectal tumor incidence in those ages 50 to 64 years was stable in most states. Among adults aged <50 years, CRC incidence rates increased by 22% from 2000 to 2013, driven solely by tumors in the distal colon (IRR, 1.24; 95% CI, 1.13-1.35) and rectum (IRR, 1.22; 95% CI, 1.13-1.31). Similar to incidence patterns, CRC death rates decreased by 34% among individuals aged ≥50 years during 2000 through 2014, but increased by 13% in those aged <50 years. Progress against CRC can be accelerated by increasing initiation of screening at age 50 years (average risk) or earlier (eg, family history of CRC/advanced adenomas) and eliminating disparities in high-quality treatment. In addition, research is needed to elucidate causes for increasing CRC in young adults. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:177-193. © 2017 American Cancer Society.

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Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

Tiantian Sun, Dan Ma, Jixuan Han … (2017)

Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.

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Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

Yi Liu-Chittenden, Bo Huang, Joong Sup Shim … (2012)

The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

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Author and article information

Contributors

Yujing Gao:

ORCID: http://orcid.org/0000-0003-0718-4992

gaoyujing2004@126.com

Yang Guo:

ORCID: http://orcid.org/0000-0002-4763-0072

guoyang_hbmu@foxmail.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 7 May 2021

Publication date PMC-release: 7 May 2021

Publication date Collection: May 2021

Volume: 12

Issue: 5

Electronic Location Identifier: 457

Affiliations

[1 ]GRID grid.443573.2, ISNI 0000 0004 1799 2448, Department of Immunology, School of Basic Medical Sciences, , Hubei University of Medicine, ; 442000 Shiyan, Hubei P. R. China

[2 ]GRID grid.443573.2, ISNI 0000 0004 1799 2448, Hubei Key Laboratory of Embryonic Stem Cell Research, , Hubei University of Medicine, ; 442000 Shiyan, Hubei P. R. China

[3 ]GRID grid.412194.b, ISNI 0000 0004 1761 9803, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, , Ningxia Medical University, ; Yinchuan, P. R. China

Author information

Yujing Gao http://orcid.org/0000-0003-0718-4992

Yang Guo http://orcid.org/0000-0002-4763-0072

Article

Publisher ID: 3722

DOI: 10.1038/s41419-021-03722-8

PMC ID: 8105309

PubMed ID: 33963173

SO-VID: 40e2eb05-7d2f-4691-86e1-aa472626aa91

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 31 July 2020

Date revision received : 15 April 2021

Date accepted : 16 April 2021

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81702930

Award Recipient : Yang Guo

Funded by: Hubei Provincial Natural Science Foundation (2019CFB424) Biomedical Research Foundation, Hubei University of Medicine (PI201804).

Funded by: National Natural Science Foundation of China (81872395) National Natural Science Foundation of China (81660486)

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ScienceOpen disciplines: Cell biology

Keywords: oncogenes,tumour biomarkers

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ScienceOpen disciplines: Cell biology

Keywords: oncogenes, tumour biomarkers

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YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

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Most cited references 27

Colorectal cancer statistics, 2017.

Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

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