REGγ deficiency suppresses tumor progression via stabilizing CK1ε in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common malignant disease of kidney in adults. The proteasome activator REGγ was previously reported to promote the degradation of multiple important regulatory proteins and involved in the progression and development of numerous human cancers. Here, we first reported that REGγ was upregulated in RCC and its upregulation was correlated with a poor prognosis in RCC patients. REGγ depletion obviously suppressed RCC cells proliferation in vitro and in vivo. Notably, casein kinase 1ε (CK1ε) was identified as a novel target of REGγ and knockdown of CK1ε effectively abolished the effect of REGγ depletion on RCC cells growth. Importantly, we also observed that REGγ depletion activated Hippo signaling pathway via stabilizing CK1ε in RCC, indicating the cross-talk between REGγ/CK1ε axis and Hippo pathway during RCC development. In conclusion, our findings suggested that REGγ played a pivotal role in the development of RCC and maybe helpful to identify new therapeutic strategies in the treatment of RCC.

Peer Review #3 of "REG γ knockdown suppresses proliferation by inducing apoptosis and cell cycle arrest in osteosarcoma (v0.2)"

“…Murata et al found that REG γ-deficient mice display growth retardation compared with wild type mice. Meanwhile, previous studies reported that REG γ was strongly implicated in many kinds of cancer cells proliferation (Chen et al 2018;Li et al 2015a;Zhang et al 2012). Our results are consistent with these data, indicating that REG γ plays a critical role in osteosarcoma proliferation.…”

REG γ knockdown suppresses proliferation by inducing apoptosis and cell cycle arrest in osteosarcoma

“…Meanwhile, we found that proapoptotic protein (caspase-3) level was significantly increased, while antiapoptotic protein (bcl-2) was decreased following REG γ knockdown. Present results were supported by previous researches (Chen et al, 2018;Moncsek et al, 2015).…”

“…To seek further the underlying mechanism that REG γ prompting human osteosarcoma proliferation, we used RNA interference to reduce REG γ expression in MG-63 and SaoS-2 human osteosarcoma cell lines, then performed cell-cycle profile and apoptosis analysis by flow cytometry and measured the cell cycle and apoptosis related proteins level. Knockdown of REG γ lead more cells to be arrested at the G0/G1 phase in our experiments, that was parallel with other independent studies on prostate cancer cells (Chen et al, 2017) and renal carcinoma cells (Chen et al, 2018). However, another study also demonstrated that REG γ downregulation resulted in cell cycle arrest at the G2/M phase in HeLa cells (Chen et al, 2007).…”

“…Murata et al found that REG γ-deficient mice display growth retardation compared with wild type mice. Meanwhile, previous studies reported that REG γ was strongly implicated in many kinds of cancer cells proliferation (Chen et al, 2018;Li et al, 2015a;Zhang, Gan & Ren, 2012). Our results are consistent with these data, indicating that REG γ plays a critical role in osteosarcoma proliferation.…”

“…Moreover, REG γ can promote the degradation of multiple tumor suppressor proteins (Chen et al, 2007;Li et al, 2015b;Li et al, 2006;Wang et al, 2015) and maintain stability of centrosome and chromosomal (Zannini et al, 2008). Additionally, growing evidence have confirm that REG γ is overexpressed in multiple types of cancers, such as skin cancer (Li et al, 2015a), breast cancer (Yi et al, 2017), renal cell cancer (Chen et al, 2018) and thyroid carcinoma (Zhang, Gan & Ren, 2012). However, the expression and biological functions of REG γ in OS have never been elucidated.…”