{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n BIRC6, also known as Apollon or BRUCE, is a large, multifunctional protein that plays pivotal roles in cellular homeostasis by acting as both an inhibitor of apoptosis and an E2/E3 ubiquitin ligase. Its anti‐apoptotic function is largely mediated through the ubiquitination and proteasomal degradation of key pro‐apoptotic factors, including SMAC/DIABLO and caspase‐9, thereby preventing mitochondrial apoptosis and p53‐dependent cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, BIRC6 is implicated in the regulation of autophagy. Recent studies have shown that BIRC6 can control the cellular level of LC3 by cooperating with autophagy regulators to limit autophagosome formation, thus negatively modulating autophagic flux."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical functions, BIRC6 is also expressed in a circular RNA isoform (circBIRC6) that has been identified in undifferentiated human embryonic stem cells. In this context, circBIRC6 acts as a “sponge” for microRNAs such as miR‑34a and miR‑145, thereby protecting the expression of genes needed to maintain pluripotency and suppress differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similar “sponge‐like” functions have been reported in cancer cells, where altered expression of circBIRC6 correlates with tumor progression and poor clinical outcome, as observed in non–small‐cell lung cancer and hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of cancer, elevated levels of full‐length BIRC6 have been associated with enhanced survival of cancer stem cells and chemoresistance. For instance, its overexpression in colon cancer stem cells contributes to resistance against platinum‐based drugs, and in hepatocellular carcinoma, BIRC6 facilitates p53 degradation, which promotes tumor cell proliferation and survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Likewise, targeted knockdown of BIRC6 reverses these phenotypes and enhances apoptotic responses in breast cancer models, underscoring its therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, BIRC6 has also emerged as a fusion partner in rare gene rearrangements involving ALK in lung cancer, suggesting additional roles in oncogenic signaling networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, the newly described regulatory axis involving long noncoding RNAs—in which MALAT1 modulates microRNA‐140 to control BIRC6 expression—further highlights the complex network in which BIRC6 operates to influence tumor progression and metastasis in prostate cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings demonstrate that BIRC6 serves as a central node in controlling the balance between cell survival and death. Its dual roles in inhibiting apoptosis and regulating autophagy, together with its involvement in both stem cell biology and cancer chemoresistance, render BIRC6 an attractive target for novel therapeutic interventions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yanyan Hao, Keiko Sekine, Atsushi Kawabata, et al. 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