Journal
CANCER DISCOVERY
Volume 5, Issue 7, Pages 730-739Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-1329
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Funding
- Japan Science and Technology Agency (JST)
- Ministry of Education, Culture, Sports, and Technology of Japan
- Japan Society for the Promotion of Science (JSPS)
- Astellas Foundation for Research on Metabolic Disorders
- Ono Medical Research Foundation
- Uehara Memorial Foundation
- Takeda Science Foundation
- Core Research for Evolutional Science and Technology (CREST
- JST)
- Precursory Research for Embryonic Science and Technology (PRESTO
- JST)
- Grants-in-Aid for Scientific Research [26860686, 15K14947, 26253006, 26461458, 26670695, 25293332, 15H05899] Funding Source: KAKEN
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Inositol polyphosphate 4-phosphatase B (INPP4B) has been identified as a tumor suppressor mutated in human breast, ovary, and prostate cancers. The molecular mechanism underlying INPP4B's tumor-suppressive role is currently unknown. Here, we demonstrate that INPP4B restrains tumor development by dephosphorylating the PtdIns(3,4,5)P-3 that accumulates in situations of PTEN deficiency. In vitro, INPP4B directly dephosphorylates PtdIns(3,4,5)P-3. In vivo, neither inactivation of Inpp4b (Inpp4b boolean AND(/)boolean AND) nor heterozygous deletion of Pten (Pten(+/-)) in mice causes thyroid abnormalities, but a combination of these mutations induces malignant thyroid cancers with lung metastases. At the molecular level, simultaneous deletion of Inpp4b and Pten synergistically increases PtdIns(3,4,5)P-3 levels and activates AKT downstream signaling proteins in thyroid cells. We propose that the PtdIns(3,4,5)P-3 phosphatase activity of INPP4B can function as a back-up mechanism when PTEN is deficient, making INPP4B a potential novel therapeutic target for PTEN-deficient or PIK3CA-activated cancers. SIGNIFICANCE: Although INPP4B expression is reduced in several types of human cancers, our work on Inpp4B-deficient mice provides the first evidence that INPP4B is a bonafide tumor suppressor whose function is particularly important in situations of PTEN deficiency. Our biochemical data demonstrate that INPP4B directly dephosphorylates PtdIns(3,4,5)P-3. (C) 2015 AACR.
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