The long non-coding RNA keratin-7 antisense acts as a new tumor suppressor to inhibit tumorigenesis and enhance apoptosis in lung and breast cancers

• Published in: Cell death & disease 2023-04, Vol.14 (4), p.293-293, Article 293
• Main Authors: Zhao, Zhe, Meng, Mei, Yao, Jun, Zhou, Hao, Chen, Yu, Liu, Juntao, Wang, Jie, Liu, Yuxi, Qiao, Yingnan, Zhang, Mengli, Qi, Jindan, Zhang, Tong, Zhou, Zhou, Jiang, Tao, Shang, Bingxue, Zhou, Quansheng
• Format: Article
• Language: English
• Subjects: 13/95; 14/1; 38/39; 38/77; 631/337; 631/67/1612; 631/80; 64/60; 96/95; Animals; Antibodies; Antisense RNA; Antisense therapy; Antitumor agents; Apoptosis; Apoptosis - genetics; Berberine; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - pathology; Carcinogenesis; Carcinogenesis - genetics; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cisplatin; Female; Gene Expression Regulation, Neoplastic; Humans; Immunology; Keratin; Keratin-7 - genetics; Keratin-7 - metabolism; Life Sciences; Lung - metabolism; Lung cancer; Lung Neoplasms - genetics; Mice; Non-coding RNA; Proteasomes; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Tumor suppressor genes; Tumorigenesis; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05802-3

Expression of the long non-coding RNA (lncRNA) keratin-7 antisense (KRT7-AS) is downregulated in various types of cancer; however, the impact of KRT7-AS deficiency on tumorigenesis and apoptosis is enigmatic. We aim to explore the influence of KRT7-AS in carcinogenesis and apoptosis. We found that KRT7-AS was deficient in breast and lung cancers, and low levels of KRT7-AS were a poor prognostic factor in breast cancer. Cellular studies showed that silencing of KRT7-AS in lung cancer cells increased oncogenic Keratin-7 levels and enhanced tumorigenesis, but diminished cancer apoptosis of the cancer cells; by contrast, overexpression of KRT7-AS inhibited lung cancer cell tumorigenesis. Additionally, KRT7-AS sensitized cancer cells to the anti-cancer drug cisplatin, consequently enhancing cancer cell apoptosis. In vivo, KRT7-AS overexpression significantly suppressed tumor growth in xenograft mice, while silencing of KRT7-AS promoted tumor growth. Mechanistically, KRT7-AS reduced the levels of oncogenic Keratin-7 and significantly elevated amounts of the key tumor suppressor PTEN in cancer cells through directly binding to PTEN protein via its core nucleic acid motif GGCAAUGGCGG. This inhibited the ubiquitination-proteasomal degradation of PTEN protein, therefore elevating PTEN levels in cancer cells. We also found that KRT7-AS gene transcription was driven by the transcription factor RXRα; intriguingly, the small molecule berberine enhanced KRT7-AS expression, reduced tumorigenesis, and promoted apoptosis of cancer cells. Collectively, KRT7-AS functions as a new tumor suppressor and an apoptosis enhancer in lung and breast cancers, and we unraveled that the RXRα-KRT7-AS-PTEN signaling axis controls carcinogenesis and apoptosis. Our findings highlight a tumor suppressive role of endogenous KRT7-AS in cancers and an important effect the RXRα-KRT7-AS-PTEN axis on control of cancer cell tumorigenesis and apoptosis, and offer a new platform for developing novel therapeutics against cancers.