Open AccessId3 induces an Elk‐1–caspase‐8‐dependent apoptotic pathway in squamous carcinoma cells
Author(s) -
Chen YouShin,
Aubee Joseph,
DiVito Kyle A.,
Zhou Hengbo,
Zhang Weiyi,
Chou FenPi,
SimbulanRosenthal Cynthia M.,
Rosenthal Dean S.
Publication year - 2015
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.427
Subject(s) - apoptosis , biology , ectopic expression , transcription factor , cancer research , microbiology and biotechnology , e2f1 , cell culture , cell cycle , genetics , gene
Abstract Inhibitor of differentiation/ DNA ‐binding (Id) proteins are helix–loop–helix ( HLH ) transcription factors. The Id protein family (Id1–Id4) mediates tissue homeostasis by regulating cellular processes including differentiation, proliferation, and apoptosis. Ids typically function as dominant negative HLH proteins, which bind other HLH proteins and sequester them away from DNA promoter regions. Previously, we have found that Id3 induced apoptosis in immortalized human keratinocytes upon UVB exposure, consistent with its role as a tumor suppressor. To investigate the role of Id3 in malignant squamous cell carcinoma ( SCC ) cells (A431), a tetracycline‐regulated inducible system was used to induce Id3 in cell culture and mouse xenograft models. We found that upon Id3 induction, there was a decrease in cell number under low serum conditions, as well as in soft agar. Microarray, RT ‐ PCR , immunoblot, si RNA , and inhibitor studies revealed that Id3 induced expression of Elk‐1, an E‐twenty‐six (ETS)‐domain transcription factor, inducing procaspase‐8 expression and activation. Id3 deletion mutants revealed that 80 C‐terminal amino acids, including the HLH , are important for Id3‐induced apoptosis. In a mouse xenograft model, Id3 induction decreased tumor size by 30%. Using immunofluorescent analysis, we determined that the tumor size decrease was also mediated through apoptosis. Furthermore, we show that Id3 synergizes with 5‐ FU and cisplatin therapies for nonmelanoma skin cancer cells. Our studies have shown a molecular mechanism by which Id3 induces apoptosis in SCC , and this information can potentially be used to develop new treatments for SCC patients.