Abstract
Inducing apoptosis is an effective treatment for cancer. Conventional cytotoxic anticancer agents induce apoptosis primarily through activation of tumor suppressor p53 by causing DNA damage and the resulting regulation of B-cell leukemia/lymphoma-2 (BCL-2) family proteins. Therefore, the effects of these agents are limited in cancers where p53 loss-of-function mutations are common, such as triple-negative breast cancer (TNBC). Here, we demonstrate that ultraviolet (UV) light-induced p53-independent transcriptional activation of NOXA, a proapoptotic factor in the BCL-2 family, results in apoptosis induction. This UV light-induced NOXA expression was triggered by extracellular signal-regulated kinase (ERK) activity. Moreover, we identified the specific UV light-inducible DNA element of the NOXA promoter and found that this sequence is responsible for transcription factor Krüppel-like factor 4 (KLF4)-mediated induction. In p53-mutated TNBC cells, inhibition of KLF4 by RNA interference reduced NOXA expression. Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis. Therefore, our results help to clarify the molecular mechanism of DNA damage-induced apoptosis and provide support for a possible treatment method for p53-mutated cancers.
Highlights
Evasion of apoptosis is one of the hallmarks of cancer and a major mechanism for oncogenesis, tumor growth, and cellular acquisition of resistance to chemotherapy [1,2].cancer cells can develop a variety of strategies to circumvent apoptosis, such as through enhanced expression of antiapoptotic factors or decreased expression and/or loss-of-function of proapoptotic factors [3]
We found that the transcription factor Krüppel-like factor 4 (KLF4) induces p53-independent apoptosis in triple-negative breast cancer (TNBC) cells via induction of NOXA by analysis of UV light-induced apoptosis in
We showed that induction of extracellular signal-regulated kinase (ERK) and KLF4, which leads to transcriptional activation of NOXA, is involved in p53-independent apoptosis in response to DNA damage stressors such as UV light
Summary
Cancer cells can develop a variety of strategies to circumvent apoptosis, such as through enhanced expression of antiapoptotic factors or decreased expression and/or loss-of-function of proapoptotic factors [3]. In this context, resistance to apoptosis by loss of tumor suppressor p53 function is critical for tumor development [4]. By the loss or aberrant functioning of p53, insufficient elimination of cells containing DNA damage or oncogene activation can lead to cancer development. Elucidating the regulatory mechanisms that control apoptosis in cancer cells is important for the development of strategies for cancer prevention and treatment
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