Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02281-x
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Funding
- NGS core facility of the Genome Information Research Center at the Research Institute for Microbial Diseases of Osaka University
- Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [JP16K19064, JP14J10280, 26250028]
- Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [16K19064, 26250028] Funding Source: KAKEN
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p16(Ink4a) and p21(Cip1/Waf1) act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16(Ink4) and p21(Cip1/Waf1), namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16(Ink4) and p21(Cip1/Waf1) are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16(Ink4) and p21(Cip1/Waf1) reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16(Ink4a) and p21(Waf1/Cip1) and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
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