RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN

Abstract

Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene.

Long non‑coding RNA heart and neural crest derivatives expressed�2‑antisense RNA�1 overexpression inhibits the proliferation of cancer cells by reducing RUNX2 expression in triple‑negative breast cancer

“…As an oncogene, RUNX2 is frequently upregulated during the development of human cancer (20,21). Consistent with previous studies, the present study also illustrated significantly upregulated expression of RUNX2 in tumor tissues compared with that in adjacent healthy tissues in patients with TNBC.…”

CircRUNX2 through has‐miR‐203 regulates RUNX2 to prevent osteoporosis

“…RUNX2 is a member of the human RUNT related transcription factor family essential during embryogenesis for skeletal development. It was recognized on account of its oncogenic properties and many studies showed that a de‐regulating of RUNX2 function leads to progression and invasion of different tumours . Also, RUNX2 was reported to closely relate to bone formation and hypertrophic chondrocyte differentiation .…”

“…It was recognized on account of its oncogenic properties and many studies showed that a de-regulating of RUNX2 function leads to progression and invasion of different tumours. 12 Also, RUNX2 was reported to closely relate to bone formation and hypertrophic chondrocyte differentiation. 13 Some evidence showed that the down-regulated RUNX2 protein expression inhibited bone formation, and decreased bone mass.…”

BET protein inhibitor JQ1 downregulates chromatin accessibility and suppresses metastasis of gastric cancer via inactivating RUNX2/NID1 signaling

“…The motif-enrichment analysis implicated that RUNX2 was highly enriched in the opened regions of the controlled cells compared with JQ1-treating cells. RUNX2 was initially regarded as a promoter of osteoblast differentiation and was later proved to regulate the development of various tumors [31][32][33] . Guo et al 34 indicated that RUNX2 was highly expressed in human GC tissues and promoted the metastasis of GC by transcriptionally upregulating CXCR4 signaling, verifying the correlation between RUNX2 and GC progression.…”