CENPM

CENPM is a constitutive centromere-associated protein that functions as a structural pseudo-GTPase essential for kinetochore assembly and chromosome segregation. Structurally related to small GTPases but incapable of GTP binding, CENPM nucleates and stabilizes the CENP-H/I/K/M (HIKM) tetramer; disruption of the CENPM–CENP-I interface impairs kinetochore recruitment of the CENP-T/W complex and causes chromosome misalignment, placing CENPM downstream of CENP-C and upstream of CENP-T/W in the inner kinetochore assembly hierarchy (PMID:25006165). In multiple cancer types, CENPM is transcriptionally driven by E2F1 and promotes proliferation, invasion, and glycolytic reprogramming through activation of mTOR/p70S6K and PI3K/AKT signaling, while suppressing the cGAS-STING innate immune pathway (PMID:35462155, PMID:32705259, PMID:39707034, PMID:38693472). An alternative transcript of the CENPM locus encodes an HLA-A*0301-restricted minor histocompatibility antigen whose expression is regulated by B-cell activation (PMID:16391015).

1. 2006 High

   Before CENPM's centromere function was structurally understood, an alternative transcript was found to encode a minor histocompatibility antigen (mHAg), establishing that the CENPM locus has immunological relevance beyond chromosome biology.

   Evidence Allele sequencing, T-cell recognition assays, and RT-PCR in B cells with CD40L stimulation

   PMID:16391015

   Open questions at the time

   • The mHAg-encoding isoform's relationship to the canonical centromere-localized protein is unclear
   • Whether this isoform contributes to GvHD outcomes in transplant settings was not tested functionally
2. 2014 High

   Structural and biochemical work revealed that CENPM is a pseudo-GTPase that cannot bind GTP yet is essential for nucleating the HIKM tetramer; disruption of its CENP-I interface abolished kinetochore assembly of CENP-T/W, resolving the epistatic order of inner kinetochore assembly (CENP-C → CENP-M/HIKM → CENP-T/W).

   Evidence Crystal structure, biochemical reconstitution, point mutagenesis, and chromosome alignment assays in human cells

   PMID:25006165

   Open questions at the time

   • How CENPM is initially recruited to CENP-A chromatin independently of its HIKM partners is not resolved
   • Whether the pseudo-GTPase fold has residual nucleotide-sensing capacity in vivo is unknown
   • No cryo-EM or crystallographic structure of the full HIKM tetramer bound to CENP-C exists
3. 2019 Medium

   Loss-of-function studies extended CENPM's role beyond chromosome segregation, showing that CENPM knockdown in hepatocellular carcinoma suppresses proliferation, migration, and invasion while activating p53 signaling, and identified miR-1270 as a negative regulator of CENPM expression.

   Evidence siRNA knockdown, CCK-8 proliferation, flow cytometry, wound-healing/invasion assays, GSEA, and in vivo xenograft in HCC cells

   PMID:31703591

   Open questions at the time

   • The direct mechanistic link between CENPM and p53 pathway components was not biochemically defined
   • miR-1270 regulation of CENPM was shown in a single cancer type
4. 2020 Medium

   CENPM was placed upstream of mTOR/p70S6K signaling in pancreatic cancer, providing the first specific oncogenic signaling axis through which overexpressed CENPM drives proliferation and invasion.

   Evidence siRNA knockdown, Western blot for mTOR/p70S6K pathway components in pancreatic cancer cells

   PMID:32705259

   Open questions at the time

   • Whether CENPM activates mTOR directly or through an intermediate remains unknown
   • Single lab, single cancer type
5. 2022 Medium

   Two independent advances established that E2F1 transcriptionally drives CENPM expression and that CENPM activates mTOR signaling in lung adenocarcinoma, while separately showing that HPV E5 upregulates CENPM via E2F1 in HNSCC to influence mitotic progression and radiosensitivity.

   Evidence ChIP for E2F1 at the CENPM promoter; gain/loss-of-function with mTOR inhibitor rescue; radiation survival assays

   PMID:35130633 PMID:35462155

   Open questions at the time

   • Whether E2F1 is the sole or dominant transcriptional activator of CENPM in non-HPV contexts is untested
   • The mechanism by which CENPM loss increases radioresistance in HPV-positive cells is counterintuitive and unexplained
6. 2024 Medium

   Three studies broadened the oncogenic repertoire of CENPM: it physically interacts with FGL1 to promote metastasis, drives glycolytic reprogramming via an E2F1–CENPM–glycolysis axis, and suppresses the cGAS-STING innate immune pathway to prevent pyroptosis, collectively positioning CENPM at the intersection of metabolism, immune evasion, and metastasis.

   Evidence Reciprocal Co-IP and DIA proteomics for FGL1 interaction; glycolytic metabolite measurements with 2-DG rescue; cGAS-STING inhibitor rescue; in vivo xenografts across adrenocortical carcinoma, glioblastoma, and ovarian cancer models

   PMID:38693472 PMID:39707034 PMID:39778025

   Open questions at the time

   • The direct molecular mechanism linking a centromere protein to mTOR, cGAS-STING, and glycolysis remains unknown — whether these are secondary to mitotic stress is untested
   • The FGL1 interaction domain on CENPM has not been mapped
   • No study has determined whether CENPM's oncogenic functions require its centromere localization or HIKM tetramer formation

• It remains unresolved whether CENPM's diverse oncogenic signaling activities (mTOR, PI3K/AKT, cGAS-STING suppression, glycolytic reprogramming) reflect a direct moonlighting function or are indirect consequences of chromosome instability and mitotic stress caused by centromere dysfunction upon CENPM dysregulation.
• No separation-of-function mutant distinguishing centromere versus oncogenic signaling roles has been generated
• No unbiased interactome outside the kinetochore context has been performed with endogenous CENPM
• Structural basis for CENPM–FGL1 and CENPM–mTOR pathway connections is entirely unknown