Pericentromeric Satellite III transcripts induce etoposide resistance

Abstract

Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.

Satellite DNAs in Health and Disease

“…It was noticed that heat stress (HS) conditions protect cells against the toxicity of chemotherapeutic drugs, most prominently the topoisomerase 2 (TOP2) inhibitor etoposide [ 117 ]. Recent results show that in response to heat stress, human satellite III RNA recruits topoisomerase IIa (TOP2A) to nuclear stress bodies and generates resistance against the TOP2A inhibitor etoposide in lung cancer [ 118 ]. Etoposide is frequently used to treat lung cancer and it temporarily stabilizes transiently induced DNA double-stranded breaks (DSB) created by TOP2A.…”

“…The inability of TOP2A to form a complex with etoposide results in decreased DNA damage after treatment that impacts downstream DNA repair pathways. Etoposide resistance can be overcome by inhibiting human satellite III expression with epigenetic regulator BRD4 inhibitors [ 118 ]. The results show potential roles of satellite RNAs in cancer therapy resistance and suggest the therapeutic relevance of human satellite III RNA.…”

“…According to the current results, it is evident that satellite RNA can promote tumor progression by different mechanisms: inducing mutations [ 107 ], affecting epigenetic regulators [ 112 ], enhancing tumor cell proliferation [ 119 ], provoking inflammation [ 109 , 111 ] and cancer therapy resistance [ 118 ] or compromising genome integrity [ 106 , 120 ]. On the other hand, satellite transcripts can be recognized by the innate immune system, thus triggering an immune response [ 109 , 114 ].…”

Upregulation of CCNB2 and Its Perspective Mechanisms in Cerebral Ischemic Stroke and All Subtypes of Lung Cancer: A Comprehensive Study

“…Among them, TOP2A is mainly distributed in the nucleus and participates in the cell cycle pathway, which is closely related to cell proliferation and apoptosis ( Tian et al, 2021 ). By analyzing the effect of the expression level of TOP2A protein on the proliferation and invasion of tumor cells, the researchers found that the expression of TOP2A protein was closely related to the proliferation and invasion of LC cells ( Kanne et al, 2021 ). However, there are few studies on TOP2A in the nervous system.…”

LncRNAs-associated to genomic instability: A barrier to cancer therapy effectiveness

“…Early evidence showed that several genotoxic agents cause overexpression of centromeric repeats in non-cancerous murine cells ( Hedouin et al, 2017 ). Further study in humans demonstrated satellite III repeat hypomethylation in cancerous compared to normal tissue, which was associated with etoposide resistance in non-small cell lung carcinoma ( Kanne et al, 2021 ). The authors also showed that etoposide resistance is accomplished by sequestering topoisomerase 2A (TOP2A) in nuclear stress bodies.…”