{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:46:48Z","timestamp":1785836808249,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,31]]},"group-title":"Cancer Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,31]]},"abstract":"<jats:title>\n                  <jats:bold>Abstract<\/jats:bold>\n                <\/jats:title>\n                <jats:p>\n                  Neuroendocrine prostate cancer (NEPC) is a highly aggressive and therapy-resistant subtype that arises from adenocarcinoma through lineage plasticity; however, the molecular mechanisms driving this transition remain incompletely defined. Insulinoma-associated protein 1 (INSM1), a zinc-finger transcription factor and established neuroendocrine lineage marker, has been implicated in a variety of neuroendocrine malignancies, yet its functional contribution to NEPC progression is not well understood. In this study, we demonstrate that INSM1 is consistently upregulated across NEPC patient tumors and experimental models, including both ASCL1\u207a and NEUROD1\u207a molecular subtypes, as revealed by integrated bulk and single-cell transcriptomic analyses. Functional studies revealed that INSM1 is sufficient to induce and necessary to maintain neuroendocrine lineage programs in prostate cancer, as overexpression promoted and depletion suppressed neuroendocrine-associated transcriptional networks. Mechanistically, pro-neural transcription factors, including ASCL1, NEUROD1, NEUROG3, and MYCN, directly or indirectly activate INSM1 expression, positioning it as a critical downstream effector of neuroendocrine lineage specification. Therapeutically, we identify homo-harringtonine (HHT), an FDA-approved protein synthesis inhibitor, as a potent suppressor of INSM1. HHT selectively reduces viability of INSM1-high NEPC cells at nanomolar concentrations, promotes ubiquitin-mediated degradation of INSM1, and significantly inhibits tumor growth\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Notably, INSM1 depletion further enhances cellular sensitivity to HHT treatment. Collectively, our findings establish INSM1 as a key regulator of neuroendocrine plasticity and a promising therapeutic vulnerability in NEPC, providing a rationale for targeting INSM1 to suppress tumor progression.\n                <\/jats:p>","DOI":"10.64898\/2026.07.30.741780","type":"posted-content","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:55:27Z","timestamp":1785491727000},"source":"Crossref","is-referenced-by-count":0,"title":["INSM1 Regulates Neuroendocrine Plasticity and Tumor Progression in Prostate Cancer"],"prefix":"10.64898","author":[{"given":"Chiachen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Louisiana State University Health, Shreveport LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Louisiana State University Health, Shreveport LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeyaluxmy","family":"Sivalingam","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Louisiana State University Health, Shreveport LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pathology & Translational Pathobiology, LSU Health, Shreveport LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunshin","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Service, Overton Brooks VA Medical Center, Shreveport, Louisiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuping","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry, Louisiana State University Health, Shreveport LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Lan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080402151216000_2026.07.30.741780v1.1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/978-3-030-32656-2_16","article-title":"Wnt\/Beta-Catenin Signaling and Prostate Cancer Therapy Resistance","volume":"1210","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"2026080402151216000_2026.07.30.741780v1.2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-3309"},{"key":"2026080402151216000_2026.07.30.741780v1.3","doi-asserted-by":"crossref","first-page":"1191311","DOI":"10.3389\/fendo.2023.1191311","article-title":"Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution","volume":"14","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2026080402151216000_2026.07.30.741780v1.4","doi-asserted-by":"crossref","unstructured":"Iwamoto, H. , Nakagawa, R. , Makino, T. , Kadomoto, S. , Yaegashi, H. , Nohara, T. et al. 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