Cbx8 Acts Non-canonically with Wdr5 to Promote Mammary Tumorigenesis

被引：89

作者：

Chung, Chi-Yeh ^{[1
,2
,5
]}

Sun, Zhen ^{[1
,3
,5
]}

Mullokandov, Gavriel ^{[2
,5
]}

Bosch, Almudena ^{[4
]}

Qadeer, Zulekha A. ^{[1
,5
]}

Cihan, Esma ^{[1
]}

Rapp, Zachary ^{[1
]}

Parsons, Ramon ^{[1
,5
]}

Aguirre-Ghiso, Julio A. ^{[5
,6
]}

Farias, Eduardo F. ^{[6
]}

Brown, Brian D. ^{[2
,5
]}

Gaspar-Maia, Alexandre ^{[1
]}

Bernstein, Emily ^{[1
,5
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Oncol Sci, One Gustave L Levy Pl, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, One Gustave L Levy Pl, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Dev & Regenerat Biol, One Gustave L Levy Pl, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Dept Med, Div Endocrinol Diabet & Bone Dis, One Gustave L Levy Pl, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, One Gustave L Levy Pl, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Dept Med, Div Hematol & Med Oncol, One Gustave L Levy Pl, New York, NY 10029 USA

来源：

CELL REPORTS | 2016年 / 16卷 / 02期

关键词：

HUMAN BREAST-CANCER; POLYCOMB GROUP PROTEIN; STEM-CELLS; GLAND DEVELOPMENT; GENE-EXPRESSION; CHEMICAL PROBE; NOTCH; TUMORS; HETEROGENEITY; RESISTANCE;

D O I：

10.1016/j.celrep.2016.06.002

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.

引用

页码：472 / 486

页数：15

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