Abstract Oncogene-induced senescence (OIS) is regarded a tumor suppressive mechanism in normal cells. Accumulated evidences, however, demonstrate that OIS would play a role in cancer promotion through the secretion of senescence associated secretory phenotypes (SASP). The underlying mechanisms remain to be addressed. In this study, we found that c-Myc oncogene could induce senescence in human diploid lung fibroblasts and non-small cell lung cancer cells (NSCLC) without concomitant emergence of apoptosis. c-Myc-induced senescence (cMIS) caused morphological enlargement, increased F-actin and nuclear G-actin that generally detected in senescent cells. These events were found to be associated with increased expression of cofilin-1, an actin-binding protein required for actin dynamics. Transfection of c-Myc could induce cofilin-1, but transfection of truncated Myc-Nick mutant and inhibition of c-Myc reduced cofilin-1 expression. Additionally, knockdown of cofilin-1 could suppress cMIS. The chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assay showed that the endogenous c-Myc mainly bound to two out of three predicted E-boxes located in middle and proximity to the transcription initiation site of the CFL1 promoter. Interestingly, ectopic expression of c-Myc bound to all E-boxes, especially the distal one. Furthermore, the conditioned medium (CM) collected from cells with cMIS could enhance the proliferation and migration of other NSCLC cells, whereas that obtained from cofilin-1 silencing cells with forced expression of c-Myc diminished these capacities. The c-Myc transactivated cofilin-1 could also be triggered by H 2 O 2 through the middle E-box. Surprisingly, a physical interaction between c-Myc and cofilin-1 was detected, and H 2 O 2 increased this effect. Clinically, high expression of both c-Myc and CFL1 genes correlated to worse survival rates among NSCLC patients, especially those with the adenocarcinoma subtype. Taken together, the c-Myc-cofilin-1 regulatory axis would explain the mechanism of OIS promoted cancer progression, and it may be a potent target for design of treatments.
Chou et al. (Thu,) studied this question.