Linkage between Twist1 and Bmi1: Molecular mechanism of cancer metastasis/stemness and clinical implications

1. Cancer metastasis is the major cause of cancer-related death despite significant improvements in multimodal cancer therapy. Epithelial–mesenchymal transition (EMT), a major mechanism of cancer metastasis, is a process that generates cells with stem cell-like properties (cancer stemness). 2. Cancer stemness is a concept that describes a minor population of cells (cancer stem cells) residing within a tumour that are able to self-renew and are resistant to conventional therapy. The mechanisms delineating the generation of cancer stemness and its connection to cancer metastasis remain largely unknown. 3. Twist1 is an EMT regulator and increased Twist1 expression, which has prognostic significance in various human cancers, has been widely reported. Bmi1 is a critical component of polycomb repressive complex (PRC) 1, which maintains self-renewal and stemness. Bmi1 is frequently overexpressed in different types of human cancers and can induce drug resistance (Table 2). Table 2. Expression and clinical implication of Twist1 and Bmi1 in human cancers Cancer site Twist1 overexpression Bmi1 overexpression Head and neck squamous cell carcinoma Metastasis12 Poor overall survival30 Poor overall survival30 Breast carcinoma Poor overall survival64 Poor overall survival49 Cervical carcinoma Poor overall survival65 Poor overall survival50 Gastric cancer Histological type66 Poor overall survival51 Hepatocarcinomas Distant metastasis67 Recurrence52 Poor overall survival68 Non-small cell lung cancer Poor overall survival69 Tumour progression53 Poor overall survival54 Colon cancer Tumour progression70 Poor overall survival55 Poor overall survival33 Bladder cancer Poor progression-free survival71 Poor overall survival56 Oesophageal squamous cell carcinoma Distant metastasis72, 73 Poor overall survival57 Poor overall survival73 Ovarian cancer Tumour progression74 Poor overall survival58 Prostate cancer Metastasis75 Chronic myeloid leukaemia Disease progression59 Medulloblastoma Poor overall survival60 4. Recent studies have shown that Twist1 directly activates Bmi1 expression and that these two molecules function together to mediate cancer stemness and EMT. These results present a unique mechanism of EMT-induced cancer metastasis and stemness. 5. Further investigation of the mechanisms of EMT-mediated cancer metastasis and stemness will contribute to the management and treatment of metastatic cancers.