Function of ARID4B in breast cancer
Adjuvant radiotherapy or chemotherapy is a standard treatment for breast cancer patients after surgical resection of cancer. However, cancer cells commonly develop therapeutic resistance. A crucial factor that decides whether a tumor relapses or responds to these cancer therapies is the dual role of interferon (IFN) in promoting or counteracting cancer progression, respectively. A set of IFN-stimulated genes (ISGs), the so-called “IFN-related DNA damage resistance signature” (IRDS), was recently implicated in resistance to irradiation and chemotherapy in different types of cancers, including breast cancer. While irradiation and some of chemotherapy drugs cause DNA damage in cancer cells, IFN1 induces expression of IRDS that mediates DNA damage resistance to treatments. Therefore, in theory, inhibiting the IFN1 pathway could restore therapeutic sensitivity. However, indiscriminate suppression of IFN1 signaling could also constrain its anti-tumor effects, which will not provide the desired clinical efficacy to patients. Inhibiting the IRDS-mediated pro-tumor activities but reserving the IFN1-induced
anti-tumor effects could be a favorable strategy to provide major benefit to patients. To this end, understanding how the IRDS is regulated and how it protects cancer cells against therapies is urgent and important. AT-rich interaction domain 4B (ARID4B) belongs to the ARID family and is a chromatin remodeling protein. Our preliminary data demonstrate that ARID4B is highly expressed in human breast cancer and its high expression is associated with poor clinical outcomes in breast cancer patients. Knockout of ARID4B in breast cancer cell lines and mouse models compromised tumorigenesis. In addition, ablation of ARID4B reduced DNA damage repair and increased sensitivity to irradiation and DNA-damaging drugs in breast cancer cells. Mechanistically, ARID4B is required for IFN1-mediated activation of the STAT1-IRDS axis and regulates PARylation/dePARylation in breast cancer cells. The IFN1 pro-tumor effects are determined by ARID4B, because ARID4B is crucial for activation of the IFN1-STAT1-IRDS signaling pathway that regulates PARylation/dePARylation-dependent DNA damage response to promote breast cancer progression and therapeutic resistance to irradiation and DNA-damaging drugs.
Function of ARID4B in prostate cancer
Prostate cancer (PCa) is initially dependent on androgens for growth and is therefore responsive to androgen-deprivation therapy. However, patients eventually progress to an androgen-insensitive state and develop castration-resistant prostate cancer (CRPC). During progression to castration resistance, prostate cancer cells reprogram the androgen responses to deal with the diminishing level of androgen. Although second-generation antiandrogens have been approved to treat CRPC, it is common for CRPC cells to develop resistance. To date, CRPC remains uniformly fatal because there is no established therapy that cures this hormone refractory disease. Our preliminary data demonstrate
that 21% of CRPC patients have gene amplifications of AT-rich interaction domain 4B (ARID4B). In addition, ARID4B confers resistance to androgen-deprivation in prostate cancer cells. Using genetically engineered mouse models, we found that ARID4B overexpression not only promotes prostate tumorigenesis, but cooperates with PTEN loss to facilitate malignant transformation in PCa and CRPC. Mechanistically, ARID4B functions as an epigenetic regulator required for activation of notch receptor 1 (NOTCH1) expression. The NOTCH1 signaling has been shown to promote PCa growth and metastasis and sensitize prostate cancer cells to antiandrogens. ARID4B promotes PCa malignancy
progression and CRPC growth through activation of the NOTCH1 signaling pathway, and inhibition of ARID4B could prevent aggressive PCa and CRPC.