Loss of H2B monoubiquitination is associated with poor‐differentiation and enhanced malignancy of lung adenocarcinoma

Abstract

Deregulated monoubiquitination of histone H2B (H2Bub1), mainly catalyzed by E3 ubiquitin-protein ligase RNF20/RNF40 complex, may play an important role in cancer. Here we investigate potential roles of H2Bub1 and the underlying mechanisms through which it contributes to cancer development and progression in lung adenocarcinoma. We show that downregulation of H2Bub1 through RNF20 knockdown dramatically decreases H3K79 and H3K4 trimethylation in both normal and malignant lung epithelial cell lines. Concurrently, global transcriptional profiling analysis reveals that multiple tumor-associated genes such as CCND3, E2F1/2, HOXA1, Bcl2 modifying factor (BMF), Met, and Myc; and signaling pathways of cellular dedifferentiation, proliferation, adhesion, survival including p53, cadherin, Myc, and anti-apoptotic pathways are differentially expressed or significantly altered in these lung epithelial cells upon downregulation of H2Bub1. Moreover, RNF20 knockdown dramatically suppresses terminal squamous differentiation of cultured bronchial epithelial cells, and significantly enhances proliferation, migration, invasion, and cisplatin resistance of lung cancer cells. Furthermore, immunohistochemistry analysis shows that H2Bub1 is extremely low or undetectable in > 70% of 170 lung adenocarcinoma samples. Notably, statistical analysis demonstrates that loss of H2Bub1 is significantly correlated with poor differentiation in lung adenocarcinoma (P = 0.0134). In addition, patients with H2Bub1-negative cancers had a trend towards shorter survival compared with patients with H2Bub1-positive cancers. Taken together, our findings suggest that loss of H2Bub1 may enhance malignancy and promote disease progression in lung adenocarcinoma probably through modulating multiple cancer signaling pathways.

Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53

“…Moreover, H2Bub1 has also been reported to be closely involved in cancer. Most studies have indicated that the levels of H2Bub1 are decreased in cancer, and loss of H2Bub1 promotes cancer metastasis [32,33], although controversial results have been reported [34]. In addition, our group recently suggested that H2Bub1 is also a critical epigenetic marker for the regulation of autophagy.…”

“…In addition to the establishing enzymes, multiple deubiquitinases have also been identified, including USP7 [22][23][24][25], USP12 [26], USP22 [27], USP44 [28], USP46 [26], and USP49 [29]. Most studies have indicated that the levels of H2Bub1 are decreased in cancer, and loss of H2Bub1 promotes cancer metastasis [32,33], although controversial results have been reported [34]. For example, other researchers and our group have revealed the critical roles of H2Bub1 in the control of embryonic stem cell (ESC) differentiation.…”

RNF40-dependent epigenetic regulation of actin cytoskeletal dynamics is required for HER2-driven mammary tumorigenesis

“…These findings have led to the hypothesis that H2Bub1, catalyzed by the obligate heterodimeric Ring Finger Protein 20 and 40 (RNF20/RNF40) E3 ubiquitin ligase complex, has a tumor suppressive function. This hypothesis has been further supported by studies investigating the function of RNF20 and RNF40 (13–17). In contrast, we and others have uncovered tumor supportive roles of RNF20 and RNF40 in colorectal cancer (18,19) and androgen-dependent prostate cancer (20).…”

The Functional Effects of Key Driver KRAS Mutations on Gene Expression in Lung Cancer

“…In addition, DUSP6 rs2279574 gene polymorphism is thought to predict the survival time of NSCLC patients after chemotherapy (Wang et al, 2016a). Cyclin D3 gene (CCND3) is a key cell cycle gene of NSCLC, which can promote the growth of LUAD (Zhang et al, 2017). Casein kinase I epsilon (CSNK1E), a circadian rhythm gene, whose genetic variation has a very significant correlation with the risk of lung cancer (Ortega and Mas-Oliva, 1986).…”