SUMOylation of HP1α supports association with ncRNA to define responsiveness of breast cancer cells to chemotherapy.
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.
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Feng-Ming
FM
Lin
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Santosh
S
Kumar
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Jing
J
Ren
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Samaneh
S
Karami
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Shaymaa
S
Bahnassy
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
Yue
Y
Li
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Xiaofeng
X
Zheng
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jing
J
Wang
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Tasneem
T
Bawa-Khalfe
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation
D000970:Antineoplastic Agents; C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D063146:Polycomb-Group Proteins; D022661:RNA, Untranslated; D000090266:Chromobox Protein Homolog 5; D010450:Endopeptidases; C533959:SENP7 protein, human; D008025:Ligases; C570427:CBX4 protein, human
HP1α; Rad51C; SENP7; SUMO; ncRNA