Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin
Tobias Wijshake, Zhongju Zou, Beibei Chen, Lin Zhong, Guanghua Xiao, Yang Xie, John G. Doench, Lynda Bennett, Beth Levine
Clinical Sciences - QBRC
Int Med - Autophagy Rsrch Ctr
Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.
Proceedings of the National Academy of Sciences of the United States of America
Beclin 1
E-cadherin
10.1073/pnas.2020478118
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Beclin-1 Medicine & Life Sciences 100%
Cadherins Medicine & Life Sciences 79%
Clustered Regularly Interspaced Short Palindromic Repeats Medicine & Life Sciences 38%
Autophagy Medicine & Life Sciences 32%
Heterografts Medicine & Life Sciences 20%
Wijshake, T., Zou, Z., Chen, B., Zhong, L., Xiao, G., Xie, Y., Doench, J. G., Bennett, L., & Levine, B. (2021). Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin. Proceedings of the National Academy of Sciences of the United States of America, 118(5), [e2020478118]. https://doi.org/10.1073/pnas.2020478118
Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin. / Wijshake, Tobias; Zou, Zhongju; Chen, Beibei; Zhong, Lin; Xiao, Guanghua; Xie, Yang; Doench, John G.; Bennett, Lynda; Levine, Beth.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 5, e2020478118, 02.02.2021.
Wijshake, T, Zou, Z, Chen, B, Zhong, L, Xiao, G, Xie, Y, Doench, JG, Bennett, L & Levine, B 2021, 'Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 5, e2020478118. https://doi.org/10.1073/pnas.2020478118
Wijshake T, Zou Z, Chen B, Zhong L, Xiao G, Xie Y et al. Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin. Proceedings of the National Academy of Sciences of the United States of America. 2021 Feb 2;118(5). e2020478118. https://doi.org/10.1073/pnas.2020478118
Wijshake, Tobias ; Zou, Zhongju ; Chen, Beibei ; Zhong, Lin ; Xiao, Guanghua ; Xie, Yang ; Doench, John G. ; Bennett, Lynda ; Levine, Beth. / Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin. In: Proceedings of the National Academy of Sciences of the United States of America. 2021 ; Vol. 118, No. 5.
@article{f076b4d6bdf9494fae72ed2281402d76,
title = "Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin",
abstract = "Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.",
keywords = "Beclin 1, Breast cancer, E-cadherin",
author = "Tobias Wijshake and Zhongju Zou and Beibei Chen and Lin Zhong and Guanghua Xiao and Yang Xie and Doench, {John G.} and Lynda Bennett and Beth Levine",
note = "Funding Information: ACKNOWLEDGMENTS. We thank L. Nguyen for expert technical assistance, all members of the B.L. laboratory for helpful discussions, and H. Smith for assistance with manuscript preparation. This work was supported by NIH Grants U19 AI109725 and U19 AI142784 (to B.L.) and by Cancer Prevention Research Institute of Texas Grant RP120718 (to B.L.). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
doi = "10.1073/pnas.2020478118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
publisher = "National Academy of Sciences",
T1 - Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin
AU - Wijshake, Tobias
AU - Zou, Zhongju
AU - Chen, Beibei
AU - Zhong, Lin
AU - Xiao, Guanghua
AU - Xie, Yang
AU - Doench, John G.
AU - Bennett, Lynda
AU - Levine, Beth
N1 - Funding Information: ACKNOWLEDGMENTS. We thank L. Nguyen for expert technical assistance, all members of the B.L. laboratory for helpful discussions, and H. Smith for assistance with manuscript preparation. This work was supported by NIH Grants U19 AI109725 and U19 AI142784 (to B.L.) and by Cancer Prevention Research Institute of Texas Grant RP120718 (to B.L.). Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.
N2 - Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.
AB - Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.
KW - Beclin 1
KW - E-cadherin
U2 - 10.1073/pnas.2020478118
DO - 10.1073/pnas.2020478118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
M1 - e2020478118