SUMOylation of HP1α supports association with ncRNA to define responsiveness of breast cancer cells to chemotherapy

Abstract

Epigenetic reprogramming allows cancer cells to bypass normal checkpoints and potentiate aberrant proliferation. Several chromatin regulators are subject to reversible SUMO-modification but little is known about how SUMOylation of chromatin-remodelers modulates the cancer epigenome. Recently, we demonstrated that SUMO-protease SENP7L is upregulated in aggressive BCa and maintains hypoSUMOylated heterochromatin protein 1-α (HP1α). Canonical models define HP1α as a “reader” of repressive H3K9m3 marks that supports constitutive heterochromatin. It is unclear how SUMOylation affects HP1α function in BCa cells. This report shows HP1α SUMO-dynamics are closely regulated in a complex with SENP7L and SUMO-E3 Polycomb-2 (PC2/CBX4). This complex accumulates at H3K9m3 sites, hypoSUMOylates HP1α and PC2, and reduces PC2's SUMO-E3 activity. HyperSUMO conditions cause complex dissociation, SUMOylation of PC2 and HP1α, and recruitment of SUMOylated HP1α to multiple DNA-repair genes including Rad51C. SUMOylated HP1α's enrichment at euchromatin requires chromatin-bound non-coding RNA (ncRNA), reduces Rad51C protein, and increases DNA-breaks in BCa cells. Hence, HP1α SUMOylation and consistently low SENP7L increase efficacy of DNA-damaging chemotherapeutic agents. BCa patients on chemotherapy that express low SENP7L exhibit greater survival rates than patients with high SENP7L. Collectively, these studies suggest that SUMOylated HP1α is a critical epigenetic-regulator of DNA-repair in BCa that could define chemotherapy responsiveness.

Novel SUMO-Protease SENP7S Regulates β-catenin Signaling and Mammary Epithelial Cell Transformation

“…S2C,D ) and MCF7 cells ( Fig. 2B ); this is consistent with its ability to bind multiple chromatin-bound proteins 4 15 16 17 . Assessment of additional images confirmed the inverse subcellular localization of SENP7S versus SENP7L; SENP7S is predominantly cytosolic and SENP7L is nuclear ( Fig.…”

“…Like SENP7L, SENP7S processes SUMO2/3 conjugates as targeted SENP7S knockdown potentiates SUMO2/3 conjugates. SUMOylated protein targets of SENP7L include HP1α, SUMO E3 ligase PC2, and transcription factor KAP1 4 15 16 17 . In contrast, SENP7S is inefficient at deSUMOylating HP1α even when overexpressed 4 .…”

“…MCF10-2A cell proliferation was evaluated as previously described 16 . For the clonogenic assay to test anchorage-dependent proliferation, siRNA-treated MCF10-2A cells were first dissociated to generate single cells.…”

Long non-coding RNA HOXA-AS2 promotes proliferation and invasion of breast cancer by acting as a miR-520c-3p sponge

“…As the most common gynecological cancer, which has a low 5-year survival rate in patients with metastasis, breast cancer research is urgently needed to improve early diagnosis and treatment in human populations [ 35 ]. Non-coding RNA (ncRNA) has been regarded as a mechanism potentially driving breast cancer progression and metastasis and may serve as a new and more effective therapy in breast cancer [ 36 , 37 ]. Among these ncRNAs, lncRNAs, which have extensive functions in cancer development [ 38 , 39 ], have emerged as a new hot topic in early diagnosis and molecular targeted therapy [ 40 ].…”

CBX4 Expression and AFB1-Related Liver Cancer Prognosis

“…Functionally, CBX4 involves in PRC1-regulated transcription repression and post-translation modification [19][20][21][22]. Recently, increasing evidence has exhibited that the dysregulation of this gene may affect the carcinogenic process of some tumors such as HCC, colorectal cancer, breast cancer, and so on, and may be a significant prognostic biomarker [19,21,[23][24][25][26][27][28][29]. However, it is not clear whether CBX4 modify the prognosis of AFB1-related HCC.…”