Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4

Abstract

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring‐between‐Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5‐Aza‐2‐deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl‐CpG‐binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

RNF144A exerts tumor suppressor function in breast cancer through targeting YY1 for proteasomal degradation to downregulate GMFG expression

“…Our previous studies showed that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation [ 15 ] and its expression levels are associated with favorable prognosis of breast cancer patients [ 16 ]. In this study, we provide new mechanistic insights into tumor suppressor function of RNF144A in breast cancer cells.…”

“…5 and 6 ). As RNF144A is downregulated in breast cancer cell lines and tumor tissues [ 15 , 16 ], which could be partially contribute to overexpression of YY1 in breast cancer cells [ 28 ].…”

“…Consistently, loss of RNF144A contributes to carcinogen-induced bladder tumorigenesis [ 14 ]. We recently demonstrated that RNF144A is epigenetically silencing in breast cancer cells by promoter hypermethylation [ 15 ], suppresses breast cancer progression through promoting the degradation of oncoprotein heat-shock protein family A member 2 (HSPA2) [ 16 ], and regulates the sensitivity of breast cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors through modulating the degradation PARP1 [ 17 ]. Together, these results indicate that RNF144A acts as an emerging tumor suppressor, but its underlying mechanisms still remain poorly understood.…”

Unconventional protein post-translational modifications: the helmsmen in breast cancer

“…RNF144A and Parkinson protein 2 (PARK2, also known as Parkin) are members of the RBR E3 ligase family that have been identified as tumor suppressor genes in breast cancer, their low expression levels in breast cancer may be attributed to hypermethylation in their promoter [ 200 , 201 ]. RNF144A ubiquitinates and degrades the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and poly (ADP-ribose) polymerase 1 (PARP1) to inhibit the repair of DNA damage via non-homologous end joining (NHEJ) and base excision repair (BER) pathways, respectively [ 202 , 203 ].…”

Ring finger protein 19A is overexpressed in non‐small cell lung cancer and mediates p53 ubiquitin‐degradation to promote cancer growth

“… 7 Misregulation of RBR proteins often leads to diverse diseases, including various cancers. For instance, RBR E3 ligases, including Parkin, 8 RNF144A, 9 , 10 RBCK1 11 , 12 and RNF216 13 are involved in lung, breast and colorectal cancers through ubiquitin‐mediated degradation, indicating the vital function of RBR proteins in carcinogenesis.…”