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Suppression of RAD21 Induces Senescence of MDA‐MB‐231 Human Breast Cancer Cells Through RB1 Pathway Activation Via c‐Myc Downregulation
Author(s) -
Zhu Shan,
Zhao Li,
Li Yueyang,
Hou Pingfu,
Yao Ruosi,
Tan Jiang,
Liu Dongxu,
Han Liping,
Huang Baiqu,
Lu Jun,
Zhang Yu
Publication year - 2016
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25426
Subject(s) - downregulation and upregulation , senescence , gene knockdown , gene silencing , biology , microbiology and biotechnology , small interfering rna , cancer research , retinoblastoma protein , cancer cell , transfection , cancer , cell cycle , cell culture , genetics , gene
Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA‐MB‐231 human breast cancer cells. Importantly, we showed that knockdown of RAD21 resulted in the appearance of several senescent markers, including enhanced senescence‐associated β‐galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and RB1 pathway activation. Further biochemical analyses revealed that RAD21 knockdown led to the downregulation of c‐Myc and its targets, including CDK4, a negative regulator of RB1, and blockedRB1 phosphorylation (pRB1), and the RB1‐mediated transcriptional repression of E2F. Moreover, c‐Myc downregulation was partially mediated by proteasome‐dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during RAD21 knockdown‐induced senescence. Exogenous c‐Myc reconstitution rescued cells from RAD21 silencing‐induced senescence. Altogether, data arising from this study implicate a novel function of RAD21 in cellular senescence in MDA‐MB‐231 cells that is mainly dependent onRB1 pathway activation via c‐Myc downregulation. J. Cell. Biochem. 117: 1359–1369, 2016. © 2015 Wiley Periodicals, Inc.